Smooth muscle and the cardiovascular and lymphatic systems
125.e1
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In some blood vessels, notably those of the pulmonary circulation,
and in the airways and probably in other smooth muscle types, there
is evidence for heterogeneity of cell phenotype. The smooth muscle cells
of small blood vessels and bronchioles exhibit different functional
properties from those in larger vessels and airways, and may differ in
morphology, expression of signalling proteins such as ion channels, and
excitation–contraction coupling mechanisms. Even within individual
tissues there is evidence of heterogeneity. Some myofibroblast-like cells
have a function that is more secretory than contractile. The secretory
phenotype is often increased in disease (e.g. chronic severe asthma,
pulmonary hypertension) and is associated with increased proliferation
and remodelling, and with secretion of cytokines and other mediators.
Many smooth muscles seem to exhibit considerable phenotypic plastic-
ity between these contractile and secretory phenotypes (Halayko and
Solway 2001).


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which in turn attach to integrins that cross the membrane and provide rather than actin/tropomyosin. Most smooth muscles contain little or
attachment to components of the extracellular matrix (Gunst and no troponin, and instead calcium binds to calmodulin. The calcium–
Zhang 2008). calmodulin complex regulates the activity of myosin light chain kinase,
An analogous arrangement underlies cell–cell attachment at desmo- which phosphorylates myosin regulatory light chains and initiates the
somes, but here the attachment between dense plaques is provided by myosin–actin adenosine 5′-triphosphatase (ATPase) cycle. The enzy-
transmembrane cadherin glycoproteins and intracellular catenins matic activation process is therefore inherently slow. Myosin phos-
instead of integrins and talin. Mechanical deformation of the cell may phatase dephosphorylates myosin and thus promotes relaxation. The
be linked to cell signalling mechanisms via focal adhesion kinase (FAK) degree of myosin phosphorylation and therefore contraction depends
and its substrate paxillin; phosphorylation of talin and paxillin may on the relative activities of myosin light chain kinase and myosin phos-
modulate the deformability of the smooth muscle cell. Other regulatory phatase. Thus inhibition of the phosphatase, e.g. by Rho kinase, in-
proteins also associate specifically with actin, such as caldesmon and creases phosphorylation for any level of calcium (i.e. increases calcium
calponin. The cytoskeleton is not a passive structure. It adapts dynami- sensitivity). The latter is a central component of the response to many
cally to load and is modulated by cell surface receptors including constrictor agonists.
integrins and agonist binding to G-protein coupled receptors, and so
Regulation of smooth muscle
contributes to contraction (Gunst and Zhang 2008). This presumably
contributes to the low energy requirements of smooth muscle contrac- intracellular calcium
tion because dynamic reorganization of the cytoskeleton following Intracellular calcium is a key determinant of smooth muscle
active contraction allows cell shortening to be maintained without function, including contraction and also proliferation, migration and


further energy expenditure. secretion of mediators. Its regulation in smooth muscle is particularly
The ratio of actin to myosin is about eight times greater in smooth complex, and involves calcium entry via both voltage-dependent and
compared to striated muscle, reflecting the greater length of actin fila- independent ion channels, release from and reuptake into intracellu-
ments in smooth muscle. Smooth muscle myosin filaments are lar stores such as the sarcoplasmic reticulum, and modulation by
1.5–2 µm long, somewhat longer than those of striated muscle. mitochondria.
Although smooth muscle cells contain less myosin, the longer filaments
are capable of generating considerable force. The myosin filaments of
smooth muscle are also assembled differently, such that their head ORIGIN OF SMOOTH MUSCLE
regions lie symmetrically on either side of a ribbon-like filament, rather
than imposing a bipolar organization on the filament. Actin filaments, It was thought that all smooth muscle cells developed in situ exclusively
to which they bind, can thus slide along the whole length of the myosin from the splanchnopleuric mesenchyme in the walls of the anlagen of
filament during contraction. In addition, dynamic polymerization of the viscera and around the endothelium of blood vessels. However,
both myosin and actin monomers during activation can alter the length endothelial and tunica media smooth muscle cells arise from the epi-
of the contractile filaments. These differences underpin the ability of thelial plate of individual somites (Scaal and Christ 2004), and the
smooth muscle to undergo much greater changes in length than striated smooth muscle of the sphincter and dilator pupillae is derived from
muscle. Actin–myosin filament sliding generates tension, which trans- neurectoderm.
mits to focal regions of the plasma membrane, changing the cell to a Following a period of proliferation, clusters of myoblasts become
shorter, more rounded shape (see Fig. 6.3B) and often deforming the elongated in the same orientation. Dense bodies, associated with actin
nucleus to a corkscrew-like profile. and cytoskeletal filaments, appear in the cytoplasm, and the surface
Although some smooth muscles can generate as much force per unit membrane starts to acquire its specialized features, i.e. caveolae, adhe-


cross-sectional area as skeletal muscle, the force always develops much rens junctions and gap junctions. Cytoskeletal filaments extend to
more slowly than in striated muscle. Smooth muscle can contract by insert into the submembraneous dense plaques and cytoplasmic dense
more than 80%, a much greater range of shortening than the 30% or bodies. Thick filaments are seen a few days after the first appearance of
so to which striated muscle is limited. The significance of this property thin filaments and intermediate filaments, and from this time the cells
is illustrated by the urinary bladder, which is capable of emptying are able to contract. During development, dense bodies increase in
completely from an internal volume of 300 ml or more. Smooth number and further elements of the cytoskeleton are added. In addi-
muscles can maintain tension for long periods with very little expendi- tion to synthesizing the cytoskeleton and contractile apparatus, the
ture of energy. Many smooth muscle structures are able to generate differentiating cells express and secrete components of the extracellular
spontaneous contractions; examples are found in the walls of the intes- matrix.
tines, ureter and uterine tube. In a developing smooth muscle, all the cells express characteristics
of the same stage of differentiation and there are no successive waves
of differentiation. From its earliest appearance to maturity, a smooth
EXCITATION–CONTRACTION COUPLING
muscle increases several hundred-fold in mass, partly by a 2–4-fold
IN SMOOTH MUSCLE increase in the size of individual cells, but mainly by a very large
increase in cell number. Growth occurs by division of cells in every part
Excitation–contraction coupling in smooth muscle is more complex of the muscle, not just at its surface or ends. Mitosis occurs in cells in
than in skeletal or cardiac muscle, and may be electromechanical or which differentiation is already well advanced, as evidenced by the
pharmacomechanical. Electromechanical coupling involves depolariza- presence of myofilaments and membrane specializations. Mitotic
tion of the cell membrane by an action potential, and may be generated smooth muscle cells may be found at any stage of life but their numbers
when a membrane receptor, usually linked with an ion channel, is peak before birth, at a time that differs for different muscles; they are


occupied by a neurotransmitter, hormone or other blood-borne sub- rare in the adult unless the tissue is stimulated to hypertrophy (as in
stance. It is most commonly seen in unitary and phasic smooth muscles the pregnant uterus) or to repair. The ability of mature cells to undergo
such as those of the viscera, with transmission of electrical excitation mitosis therefore differs between the three major types of muscle: skel-
from cell to cell via gap junctions. In some types of smooth muscle etal muscle cells cannot divide at all after differentiation; cardiac muscle
depolarization may be the consequence of other stimuli, such as cells can divide but only before birth; and smooth muscle cells appear
cooling, stretch and even light. to remain capable of division throughout life.
Pharmacomechanical coupling is a receptor-mediated and G-protein During the early stages of development, smooth muscle expresses
coupled process, and is the major mechanism in tonic smooth muscles embryonic and non-muscle isoforms of myosin. The proportions of
such as in the vasculature and airways. It may involve several pathways, these isoforms decrease progressively. Initially, SM-1 is the dominant or
including formation of inositol trisphosphate, which triggers intracel- exclusive smooth muscle heavy chain isoform and the SM-2 isoform
lular calcium release from the sarcoplasmic reticulum, activation of becomes more established later. For a review of the development of
voltage-independent calcium channels in the sarcolemma, and depo- vascular smooth muscle, see Owens et al (2004).
larization causing activation of voltage-dependent calcium channels
(reviewed in Berridge (2008)). In addition, many receptors also couple
to kinases that modulate contraction in a calcium-independent fashion, SMOOTH MUSCLE REMODELLING IN DISEASE
either via myosin phosphatase (see below) or via the actin cytoskeleton
(see above). The extent to which any of these pathways contributes to The ability of smooth muscle cells to divide and change phenotype
activation varies between different types of smooth muscle. throughout life means that smooth muscle has significant plasticity and
Whilst the regulation of contraction of smooth muscle is largely can adapt to changing needs and stimuli, e.g. in the walls of the uterus
calcium-dependent, in contrast to cardiac and skeletal muscle, the during pregnancy. This can, however, have detrimental consequences in


effects of an elevation of intracellular calcium are mediated via myosin disease.


Smooth muscle and the cardiovascular and lymphatic systems
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The arrangement of peripheral signalling microdomains (see above)
is vital to this process. Sequential release from inositol trisphosphate
receptors and calcium-sensitive ryanodine receptors (calcium release
channels) in the sarcoplasmic reticulum, together with reuptake via the
sarco-endoplasmic reticulum calcium ATPase (SERCA), give rise to slow
calcium oscillations; it is now thought that the rate of oscillations,
rather than the average level of calcium, is the prime driver for smooth
muscle function, including contraction and activation of gene transcrip-
tion (Berridge 2008).
Sustained stress (physical or oxidative), tissue damage, inflammatory
mediators and other stimuli can promote enhanced growth, apoptosis
(programmed cell death, p. 26) and switching to a more secretory
phenotype (see above). Increased mediator release as a result of switch-
ing to a more secretory phenotype can potentiate such changes and
attract inflammatory cells, resulting in a positive feedback loop. Chronic
disease and inflammation can therefore lead to extensive smooth
muscle remodelling, a major contributing factor to, for example,
chronic asthma and pulmonary hypertension, which significantly wors-
ens the conditions (Mahn et al 2010, Stenmark et al 2006). Peripheral
vascular remodelling may also occur in essential hypertension and
diabetes.


Cardiovascular and lymphatic systems
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venous blood transferring solutes to the afferent arterial supply; this
CARDIOVASCULAR AND LYMPHATIC SYSTEMS
mechanism is essential for concentration of the urine.
Arteries and veins are named primarily according to their anatomical
GENERAL ORGANIZATION position. In functional terms, four main classes of vessel are described:
conducting and distributing vessels (large arteries), resistance vessels
Cells of peripheral blood, suspended in plasma, circulate through the (small arteries but mainly arterioles), exchange vessels (capillaries, sinu-
body in the blood vascular system. Fluid and solutes exchange between soids and small venules) and capacitance vessels (veins). Structurally,
the plasma and interstitium across capillaries and small venules. Excess arteries can also be divided into elastic and muscular types. Although
interstitial fluid from peripheral tissues returns to the blood vascular muscle cells and elastic tissue are present in all arteries, the relative
system via the lymphatic system, which also provides a channel for the amount of elastic material is greatest in the largest vessels, whereas the
migration of leukocytes and the absorption of certain nutrients from relative amount of smooth muscle increases progressively towards the
the gut. smallest arteries.
The cardiovascular system carries nutrients, oxygen, hormones, etc. The large conducting arteries that arise from the heart, together with
throughout the body and the blood redistributes and disperses heat. As their main branches, are characterized by the predominantly elastic
a consequence of the hydrostatic pressure, the system also has mechani- properties of their walls. Distributing vessels are smaller arteries sup-
cal effects, such as maintaining tissue turgidity. Blood circulates within plying the individual organs, and their walls are characterized by a
a system made up of the heart, the central pump and main motor of well-developed muscular component. Resistance vessels include the
the system; arteries, which lead away from the heart and carry the blood smallest arteries and arterioles, and are highly muscularized. They
to the periphery; and veins, which return the blood to the heart. The provide the major part of peripheral resistance to blood flow and so
heart is essentially a pair of muscular pumps, one feeding the pulmonary cause the largest drop in blood pressure before the blood flows into the
circulation, which is responsible for gas exchange in the lungs and has tissue capillary beds.


a low hydrostatic pressure, and the other feeding the systemic circula- Capillaries, sinusoids and small (postcapillary) venules are
tion, which has a high hydrostatic pressure and serves the rest of the collectively termed exchange vessels. Their thin walls allow exchange
body. With limited exceptions, both circulations form a closed system between blood and the interstitial fluid that surrounds all cells: this is
of tubes, so that blood per se does not usually leave the circulation. the essential function of a circulatory system. Arterioles, capillaries and
From the centre to the periphery, the vascular tree shows three main venules constitute the microvasculature, the structural basis of the
modifications. The arteries increase in number by repeated bifurcation microcirculation.
and by sending out side branches, in both the systemic and the pulmo- Larger venules and veins form an extensive but variable, large-
nary circulation. For example, the aorta, which carries blood from the volume, low-pressure system of vessels conveying blood back to the
heart to the systemic circulation, gives rise to about 4 × 106 arterioles heart. Their high capacitance is due to the significant distensibility
and four times as many capillaries. The arteries also decrease in diam- (compliance) of their walls, so that the content of blood is high even
eter, although not to the same extent as their increase in number, so that at low pressures. Veins contain the greatest proportion of blood, reflect-
a hypothetical cross-section of all the vessels will show an increase in ing their large relative volume.
total area with increasing distance from the heart. At its emergence from Blood from the gastrointestinal tract (with the exception of the lower
the heart, the aorta of an adult man has an outer diameter of approxi- part of the anal canal) and from the spleen, pancreas and gallbladder
mately 30 mm (cross-sectional area of nearly 7 cm2). The diameter drains to the liver via the portal vein. The portal vein ramifies within
decreases along the arterial tree until it is as little as 10 µm in arterioles the substance of the liver like an artery and ends in the hepatic sinu-
(each with a cross-sectional area of about 80 µm2). However, given the soids. These drain into the hepatic veins, which in turn drain into the


enormous number of arterioles, the total cross-sectional area at this inferior vena cava. Blood supplying the abdominal organs thus passes
level is approximately 150 cm2, more than 200 times that of the aorta. through two sets of capillaries before it returns to the heart. The first
As a result, blood flow is faster near the heart than at the periphery. provides the organs with oxygenated blood, and the second carries
The walls of arteries decrease in thickness towards the periphery, deoxygenated blood, rich in absorption products from the intestine,
although this is not as substantial as the reduction in vessel diameter. through the liver parenchyma. A venous portal circulation also connects
Consequently, in the smallest arteries (arterioles), the thickness of the the median eminence and infundibulum of the hypothalamus with the
wall represents about half the outer radius of the vessel, whereas in a adenohypophysis. In essence, a venous portal system is a capillary
large vessel it represents between one-fifteenth and one-fifth, e.g. in the network that lies between two veins, instead of between an artery and
thoracic aorta the radius is approximately 17 mm and the wall thick- a vein, which is the more usual arrangement in the circulation. A capil-
ness 1.1 mm. lary network may also be interposed between two arteries, e.g. in the
Venules, which return blood from the capillaries, converge on each renal glomeruli, where the glomerular capillary bed lies between affer-
other, forming a progressively smaller number of veins of increasingly ent and efferent arterioles. This maintains a relatively high-pressure
large size. As with arteries, the hypothetical total cross-sectional area of system, which is important for renal filtration.
all veins at a given level reduces nearer to the heart. Eventually, only A parallel circulatory system is provided by the lymphatic vessels and
the two largest veins, the superior and inferior venae cavae, open into lymph nodes. Lymphatic vessels originate in peripheral tissues as blind-
the heart from the systemic circulation. A similar pattern is found ended endothelial tubes that collect excess fluid from the interstitial
in the pulmonary circulation but here the vascular loop is shorter and spaces between cells and conduct it as lymph. Lymph is returned to the


has fewer branch points, and consequently, the number of vessels is blood vascular system via lymphatic vessels, which converge on the
smaller than in the systemic circulation. The total end-to-end length of large veins in the root of the neck.
the vascular network in a typical adult is twice the circumference of the The development of blood vessels is described in Chapter 13.
earth.
Large arteries, such as the thoracic aorta and subclavian, axillary, General features of vessel walls
femoral and popliteal arteries, lie close to a single vein that drains the
same territory as that supplied by the artery. Other arteries are usually
All blood vessels, with the exception of capillaries and venules, have
flanked by two veins, satellite veins (venae comitantes), which lie on
walls consisting of three concentric layers (tunicae) (see Fig. 6.8). The
either side of the artery and have numerous cross-connections; the
intima (tunica intima) is the innermost layer. Its main component, the
whole is enclosed in a single connective tissue sheath. The artery and
endothelium, lines the entire vascular tree, including the heart and
the two satellite veins are often associated with a nerve, and when they
lymphatic vessels. The media (tunica media) contains muscle cells,
are surrounded by a common connective tissue sheath they form a
elastic fibres and collagen. While it is by far the thickest layer in arteries,
neurovascular bundle.
the media is absent in capillaries and is comparatively thin in veins.
The close association between the larger arteries and veins in the
The adventitia (tunica adventitia) is the outer coat of the vessel and
limbs allows counterflow exchange of heat. This mechanism promotes
consists of connective tissue, nerves and vessel capillaries (vasa
heat transfer from arterial to venous blood and thus helps to preserve
vasorum). It links the vessels to the surrounding tissues. Vessels differ
body heat. Counterflow heat exchange systems are found in certain
in the relative thicknesses and detailed compositions of these layers.
organs, e.g. in the testis, where the pampiniform plexus of veins sur-
rounds the testicular artery (this arrangement not only conserves body
Large elastic arteries
heat, but also maintains the temperature of the testis below average


body temperature). Counterflow exchange mechanisms are found in
the microcirculation, as in the arterial and venous sinusoids of the vasa The aorta and its largest branches (brachiocephalic, common carotid,
recta in the renal medulla. Here, countercurrent exchange retains solutes subclavian and common iliac arteries) are large elastic arteries that
at a high concentration in the medullary interstitium, with efferent conduct blood to the medium-sized distributing arteries.


SmooTH muSClE And THE CARdiovASCulAR And lymPHATiC SySTEmS
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The intima is made of an endothelium, resting on a basal lamina,
and a subendothelial connective tissue layer. The endothelial cells are
flat, elongated and polygonal in outline, with their long axes parallel
to the direction of blood flow (see Fig. 6.17). The subendothelial layer
is well developed, contains elastic fibres and type I collagen fibrils,
fibroblasts and small, smooth muscle-like myointimal cells. The latter
accumulate lipid with age, and in an extreme form this contributes to
atherosclerosis. Thickening of the intima progresses with age and is
more marked in the distal than in the proximal segment of the aorta.
A prominent internal elastic lamina, sometimes split, lies between
intima and media. This lamina is smooth, measures about 1 µm in
thickness, and, with the elastic lamellae of the media, is stretched under
the effect of systolic pressure, recoiling elastically in diastole. Elastic
arteries can thus sustain continuous blood flow despite the pulsatile
cardiac output, and smooth out the cyclical pressure wave. The media
has a markedly layered structure, in which fenestrated layers of elastin
(elastic lamellae) alternate with interlamellar smooth muscle cells (Fig.
6.6), collagen and fine elastic fibres. The arrangement is very regular,
such that each elastic lamella and adjacent interlamellar zone is regarded
as a ‘lamellar unit’ of the media. In the human aorta there are approxi-
mately 52 lamellar units, measuring about 11 µm in thickness. Number
and thickness of lamellar units increases during postnatal development, Fig. 6.6 Elastic artery (human aorta), stained for elastic fibres. The dense
from 40 at birth. staining of the internal elastic lamina is seen close to the luminal surface
The adventitia is well developed. In addition to collagen and elastic (top); elastic lamellae fill the tunica media and merge with the external
fibres, it contains flattened fibroblasts with extremely long, thin pro- elastic lamina at its junction with the collagenous adventitia (red fibres,


cesses, macrophages and mast cells, nerve bundles and lymphatic below). Compare with Figure 6.20. van Gieson stain. (Courtesy of Mr
vessels. The vasa vasorum is usually confined to the adventitia. Peter Helliwell and the late Dr Joseph Mathew, Department of
Histopathology, Royal Cornwall Hospitals Trust, UK.)
Muscular arteries
Muscular arteries are characterized by the predominance of smooth
muscle in the media (Fig. 6.7). The intima consists of an endothelium, I
similar to that of elastic arteries, which rests on a basal lamina and
subendothelial connective tissue. The internal elastic lamina (see Fig.
6.7; Fig. 6.8) is a distinct, thin layer, sometimes duplicated and occa-
sionally absent. It is thrown into wavy folds as a result of contraction of M
smooth muscle in the media. Some 75% of the mass of the media con-
sists of smooth muscle cells that run spirally or circumferentially around
the vessel wall. The relative amount of extracellular matrix is therefore
less than in large arteries, although fine elastic fibres that run mainly
parallel to the muscle cells are present. An external elastic lamina, com-
posed of sheets of elastic fibres, forms a less compact layer than the
internal lamina, and separates the media from the adventitia in larger
A
muscular arteries. The adventitia is made of fibroelastic connective
tissue, and can be as thick as the media in the smaller arteries. The inner
part of the adventitia contains more elastic than collagen fibres.
V
Arterioles
Fig. 6.7 The wall of a human muscular artery. The intima (I) forms the
innermost layer, lined by an endothelium (arrowhead) and separated from
In arterioles (Figs 6.9–6.10), the endothelial cells are smaller than in the middle muscular layer, the media (M), by an internal elastic lamina
large arteries, but their nuclear region is thicker and often projects mark- (short arrow). A more diffuse external elastic lamina (long arrow) divides
edly into the lumen. The nuclei are elongated and orientated parallel the media from the outermost collagenous adventitia (A), within which lie


to the vessel length, as is the long axis of the cell. The basal surface of the vasa vasorum (V). (Courtesy of Mr Peter Helliwell and the late Dr
the endothelium contacts a basal lamina, but an internal elastic lamina Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals
is either absent or highly fenestrated and traversed by cytoplasmic proc- Trust, UK.)
esses of muscle or endothelial cells. The muscle cells are larger in
cytoplasmic volume than those in the walls of large arteries and form
a layer one or two cells thick. They are arranged circumferentially and
are tightly wound around the endothelium. In the smallest arterioles
each cell makes several turns, producing extensive apposition between Nervi vasorum
parts of the same cell. Contraction of the muscle constricts the lumen, Vasa vasorum
and so controls blood flow into the capillary bed; arterioles thus act
External elastic
functionally as precapillary sphincters, even though the absence of an lamina
anatomically delineated sphincter means that the term is no longer
commonly used. Contraction of arterioles is primarily regulated by Tunica adventitia
local vasoactive and metabolic factors, but can also be controlled by Tunica media
central mechanisms. Internal elastic
lamina
Arterioles are usually densely innervated by sympathetic fibres, via
Tunica intima
small bundles of varicose axons packed with transmitter vesicles, mostly
of the adrenergic type. The distance between axolemma and muscle Endothelium of
tunica intima
cell membrane can be as little as 50–100 nm and the gap is occupied
Lumen
only by a basal lamina. Autonomic neuromuscular junctions are very
Lymphatic vessel
common in arterioles. Arteriolar adventitia is very thin.
Basal lamina of
endothelium
Capillaries
Subendothelial
connective tissue
The capillary wall (Fig. 6.11) is formed by an endothelium and its basal Fig. 6.8 The principal structural features of the larger blood vessels as
lamina, plus a few isolated pericytes. Capillaries are the vessels closest seen in a muscular artery.


Cardiovascular and lymphatic systems
129
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RETPAHC
V
L
A
Fig. 6.9 An arteriole (A) and accompanying venule (V) and lymphatic
vessel (L) (with a valve, arrow) in adipose tissue around a lymph node
(human). Note the relative thicknesses of the vessel walls, in comparison
with the diameters of their lumens. (Courtesy of Mr Peter Helliwell and the
late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall
Hospitals Trust, UK.)
Fig. 6.11 Transmission electron micrograph of a capillary in a human
muscle biopsy specimen. An endothelial cell with its nucleus in the plane
of section forms adherens junctions (long arrows) with either a second
cell or an extension of itself. The cytoplasm contains numerous
AA transcytotic vesicles (short arrows). A basal lamina surrounds the
capillary. (Courtesy of Dr Bart Wagner, Histopathology Department,
Sheffield Teaching Hospitals, UK.)
N
SS
MM
N
SS
E
Fig. 6.12 Expanded sinusoids (S), typical of endocrine glands and certain
other tissues, are seen here containing erythrocytes (orange) in the
adenohypophysis. Endocrine cells stain either blue or reddish-brown, or
Fig. 6.10 A transmission electron micrograph of a small arteriole in the are poorly stained in this trichrome preparation.
epineurium of a peripheral nerve. The vessel lumen contains erythrocytes
and is lined by endothelial cells (with nuclei, N, projecting into the lumen);
tions, albeit relatively slowly. Their passage is further limited in brain,
note the electron-lucent internal elastic lamina (pale, wavy line, arrow),
thymic cortex and testis by particularly tight junctions.
the media containing densely filamentous smooth muscle cells (M) and
Endothelial cells of some capillaries have fenestrations, or pores,
the connective tissue of the adventitia (A) merging with that of the
epineurium (E). (Courtesy of Dr Bart Wagner, Histopathology Department, through their cytoplasm, which facilitate diffusion. Fenestrations are
Sheffield Teaching Hospitals, UK.) approximately circular and 50–100 nm in diameter, and at their edge


the luminal and abluminal membranes of the endothelial cell come
into contact. The fenestration itself is usually occupied by a thin,
to the tissue they supply and their wall constitutes a minimal barrier electron-dense diaphragm containing glycoprotein PV-1, which restricts
between blood and the surrounding tissues. Capillary structure varies passage of large molecules such as proteins. Fenestrated capillaries
in different locations. Capillaries measure 4–8 µm in diameter (much occur in intestinal mucosae, endocrine and exocrine glands, and renal
more in the case of sinusoids) and are hundreds of microns long. Their glomeruli, where they may lack a diaphragm. Fenestrations are almost
lumen is just large enough to admit the passage of single blood cells, invariably present in capillaries that lie close to an epithelium, includ-
usually with considerable deformation. Typically a single endothelial ing the skin.
cell forms the wall of a capillary, and there are junctional complexes
Sinusoids
between extensions of the same cell.
Endothelial cells are joined by tight junctions (occluding junctions,
zonulae adherentes), forming a diffusion barrier. Capillary permeability Sinusoids are expanded capillaries (Fig. 6.12), and are large and irregu-
varies greatly among tissues and is correlated largely with the type of lar in shape. They have true discontinuities in their walls, allowing
endothelium. The majority of tissues, including brain, muscle, lung and intimate contact between blood and the parenchyma. The discontinui-
connective tissues, contain capillaries with a continuous, unbroken ties are formed by gaps between fenestrated endothelial cells, such that
layer of endothelium (continuous endothelium). This is impermeable the sinusoidal lining, and sometimes also the basal lamina, is incom-
to proteins, although electrolytes can diffuse through the tight junc- plete. Sinusoids occur in large numbers in the liver (where a basal


SmooTH muSClE And THE CARdiovASCulAR And lymPHATiC SySTEmS
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noiTCES
lamina is completely absent), spleen, bone marrow, adenohypophysis pial and retinal veins, veins of trabecular bone and the venous spaces
(see Fig. 6.12) and suprarenal medulla. of erectile tissue; these veins consist of endothelium supported by vari-
able amounts of connective tissue. Distinction between the media and
Venules adventitial layers is often difficult, and a discrete internal elastic lamina
is absent.
Tethering of some veins to connective tissue fasciae and other sur-
When two or more capillaries converge, the resulting vessel is larger
rounding tissues may prevent collapse of the vessel even under negative
(10–30 µm) and is known as a venule (postcapillary venule). Venules
pressure (e.g. in the cranium). Pressure within the venous system does
(see Fig. 6.9) are essentially tubes of flat, oval or polygonal endothelial
not normally exceed 5 mmHg, and it decreases as the veins grow larger
cells surrounded by basal lamina and, in the larger vessels, by a delicate
and fewer in number, approaching zero close to the heart. As they
adventitia of a few fibroblasts and collagen fibres mainly running lon-
contain only a small amount of muscle and commonly have a large
gitudinally. Pericytes (see Fig. 6.21) support the walls of these venules.
calibre, veins have limited influence on blood flow. However, venocon-
Postcapillary venules are sites of leukocyte migration. In venules of
striction is an important component of the baroreceptor reflex because
mucosa-associated lymphoid tissue (MALT), particularly of the gut and
it reduces vein compliance and therefore capacity, effectively mobilizing
bronchi, and in the lymph nodes and thymus, endothelial cells are
blood to maintain or increase central venous pressure, and hence
taller and have intercellular junctions through which lymphocytes and
cardiac output. A sudden fall in blood volume, e.g. following a haemor-
other blood components can readily pass. These are known as high
rhage, also initiates the elastic recoil and reflex constriction of veins, in


endothelial venules (HEVs) (see Figs 6.18–6.19). Elsewhere, venules are
order to compensate for the blood loss and maintain central venous
believed to be a major site where migration of neutrophils, macro-
pressure and venous return to the heart. Vasoconstriction in cutaneous
phages and other leukocytes into extravascular spaces occurs, and where
veins in response to cooling is important in thermoregulation.
neutrophils may temporarily attach, forming marginated pools.
Most veins have valves to prevent reflux of blood (Figs 6.13–6.14).
In general, the endothelium of venules has few tight junctions and
A valve is formed by an inward projection of the intima, strengthened
is relatively permeable. The intercellular junctions of venules are
by collagen and elastic fibres, and covered by endothelium that differs
sensitive to inflammatory agents, which increase their permeability to
in orientation on its two surfaces. Surfaces facing the vessel wall have
fluids and defensive cells, and facilitate leukocyte extravasation by
transversely arranged endothelial cells, whereas on the luminal surface
diapedesis.
of the valve, over which the main stream of blood flows, cells are
Venules do not acquire musculature until they are about 50 µm in
arranged longitudinally in the direction of flow. Most commonly two,
outer diameter, when they are known as muscular venules. This distinc-
or occasionally three, valves lie opposite one another; sometimes only
tion is important because postcapillary venules, which lack muscle in
one is present. They are found in small veins or where tributaries join
their walls, are as permeable to solutes as capillaries and are thus part
of the microcirculatory bed. At the level of the postcapillary venule the
cross-sectional area of the vascular tree is at its maximum, and there is
a dramatic fall in pressure (from 25 mmHg in the capillary to approxi-
mately 5 mmHg). Muscular venules converge to produce a series of
veins of progressively larger diameter. Venules and veins are capacitance Femoral vein
vessels, i.e. they have thin distensible walls that can hold a large volume
of blood and accommodate luminal pressure changes.


Fluid exchange in the microvasculature Orifice of tributary
The microvasculature is important for the creation and maintenance of
the interstitial fluid that bathes the cells. The thin walls of capillaries
and small venules allow easy diffusion of fluid and most small mole- Long saphenous vein
cules, but the endothelial barrier prevents movement of proteins;
consequently, plasma and interstitial fluid have almost identical com-
positions, except that the latter contains very little protein. Fluid transfer
across these exchange vessels is driven by the balance between the
hydrostatic pressure (i.e. blood pressure within them) forcing fluid into Cusp
the tissues, and the oncotic pressure (colloidal osmotic pressure, reflect-
ing the difference in protein concentrations) drawing fluid back into
the vessels. These ‘Starling forces’ are normally closely balanced, so dif-
ferences in hydrostatic pressure mean that fluid tends to be filtered into
the tissue at the arterial side of the exchange vessels and largely reab-
Fig. 6.13 The upper portions of the femoral and long saphenous veins
sorbed at the venous side. The balance forms lymph. Disruption of the laid open to show the valves, at about two-thirds of their natural size.
balance (e.g. high venous pressure in the feet) can lead to accumulation
of tissue fluid (oedema) and swelling.
Inflammation and endothelial permeability
Inflammatory mediators increase the permeability of capillaries and
small venules by causing contraction of endothelial cells and so loosen-
ing tight junctions. This facilitates leukocyte extravasation by diapedesis
but also disrupts normal barrier function, allowing extravasation of
protein and fluids. The consequence is tissue oedema and the swelling
that is commonly associated with inflammation. There is considerable
cross-talk between endothelial cells and cells of the immune system.
Veins
Veins are characterized by a relatively thin wall in comparison to arteries
of similar size and by a large capacitance. Wall thickness is not corre-
lated exactly with the size of the vein and varies in different regions,
e.g. the wall is thicker in veins of the leg than it is in veins of a similar
size in the arm.
The structural plan of the wall is similar to that of other vessels,
except that the amount of muscle is considerably less than in arteries,


while collagen and, in some veins, elastic fibres predominate. In most Fig. 6.14 A valve in a human small vein, formed from flap-like extensions
veins, e.g. those of the limbs, the muscle is arranged approximately of the intima that close when pressure increases on the proximal side,
circularly. Longitudinal muscle is present in the iliac, brachiocephalic, preventing backflow. (Courtesy of Mr Peter Helliwell and the late Dr
portal and renal veins and in the superior and inferior venae cavae. Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals
Muscle is absent in the maternal placental veins, dural venous sinuses, Trust, UK.)


Cardiovascular and lymphatic systems
131
6
RETPAHC
A B
C
C
TC
TC
Position of functional
precapillary sphincter
Collecting
venule
Terminal
arteriole
Fig. 6.15 A, A microcirculatory unit, showing a terminal arteriole, thoroughfare channels (TC) formed of metarterioles, capillaries (C) and collecting
venule. The distribution of smooth muscle cells and one of the precapillary sites where perfusion of the capillary bed is regulated are also shown. B, An
arteriovenous anastomosis. Note the thick wall of the anastomotic channel composed of layers of modified smooth muscle cells.
larger veins. The valves are semilunar (cusps) and attached by their
convex edges to the venous wall. Their concave margins are directed
with the flow and lie against the wall as long as flow is towards the
heart. When blood flow reverses, the valves close and blood fills an
expanded region of the wall, a sinus, on the cardiac side of the closed
valve. This may give a ‘knotted’ (varicose) appearance to the distended
veins, if these have many valves. In the limbs, especially the legs where
venous return is against gravity, valves are of great importance in aiding
venous flow. Blood is moved towards the heart by the intermittent pres-
sure produced by contractions of the surrounding muscles (the muscle
A
pump). Valves are absent in the veins of the thorax and abdomen.
AC
VASCULAR SHUNTS AND ANASTOMOSES
Arteriovenous shunts and anastomoses
V
Communications between the arterial and venous systems are found in
many regions of the body. In some parts of the microcirculation (e.g.
in the mesenteries), the capillary circulation can be bypassed by wider Fig. 6.16 A digital arteriovenous anastomosis, prepared by intravascular
thoroughfare channels formed by metarterioles (Fig. 6.15A). These perfusion of stain in a full-thickness specimen of skin, followed by
have similarities to both capillaries and the smallest arterioles, and have clearance. The heavily stained, thick-walled, tortuous anastomotic


channels (AC) contrast with the central arterial stem (A) and the thin-
a discontinuous layer of smooth muscle in their walls. Metarterioles can
walled venous (V) outflow channels. (Courtesy of the late Professor RT
deliver blood directly to venules or to a capillary bed, according to local
Grant, GKT School of Medicine, London.)
demand and conditions. When functional demand is low, blood flow
is largely limited to the bypass channel. Periodic opening and closing
of different arterioles irrigates different parts of the capillary network.
The number of capillaries in individual microvascular units and the size newborn child, there are few arteriovenous anastomoses but they
of their mesh determine the degree of vascularity of a tissue; the small- develop rapidly during the early years. In old age they atrophy, sclerose
est meshes occur in the lungs and the choroid of the eye. and diminish in number. These factors may contribute to the less effi-
Arteriovenous anastomoses (Fig. 6.15B) are direct connections cient temperature regulation that occurs at the two extremes of age.
between smaller arteries and veins. Connecting vessels may be straight In the skin of the hands and feet, especially in digital pads and nail
or coiled, and often possess a thick muscular tunic. Under sympathetic beds (see Fig. 7.18), anastomoses form a large number of small units
control, the vessel is able to close completely, diverting blood into the termed glomera. Each glomus organ has one or more afferent arteries,
capillary bed. When patent, the vessel carries blood from artery to vein, stemming from branches of cutaneous arteries that approach the
partially or completely excluding the capillary bed from the circulation. surface. The afferent artery gives off a number of fine periglomeral
Simple arteriovenous anastomoses are widespread and occur notably branches and then immediately enlarges, makes a sinuous curve, and
in the skin of the nose, lips and ears, nasal and gastrointestinal mucosae, narrows again into a short, funnel-shaped vein that opens at right angles
erectile tissue, tongue, thyroid gland and sympathetic ganglia. In the into a collecting vein (Fig. 6.16).


SmooTH muSClE And THE CARdiovASCulAR And lymPHATiC SySTEmS
132
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noiTCES
Arterial anastomoses
Arteries can be joined to each other by an anastomosis, so that one can
supply the territory of the other. An end-to-end anastomosis occurs
when two arteries communicate directly, e.g. the uterine and ovarian
arteries, the right and left gastro-epiploic arteries, the ulnar artery and
the superficial palmar branch of the radial artery. Anastomosis by con-
vergence occurs when two arteries converge and merge, as happens
when the vertebral arteries form the basilar artery at the base of the
brain. A transverse anastomosis occurs when a short arterial vessel links
two large arteries transversely, e.g. the anastomoses between the two
anterior cerebral arteries; the posterior tibial artery and the fibular
artery; and the radial and ulnar arteries at the wrist.
The angiosome concept
and vascular territories
The blood supply to the skin and underlying tissues has been mapped
using ink injection studies, corrosion casts, dissection, perforator
mapping and two- and three-dimensional radiographic analyses of
fresh cadavers and isolated limbs injected with solutions containing
lead oxide. Fig. 6.17 A scanning electron micrograph of the luminal surface of the
Findings from these different studies all support the clinically impor- basilar artery. The tightly packed endothelial cells are elongated in the
tant concept of the angiosome, a three-dimensional block of tissue direction of blood flow. (Courtesy of Masoud Alian, University College,
supplied by a source artery, its perforating branches and their accom- London.)
panying veins (Taylor and Palmer 1987, Levy et al 2003, Taylor 2003,
Pan and Taylor 2009). Angiosomes form a complex three-dimensional autocrine growth factors in response to local hypoxia, is important in
jigsaw puzzle; some pieces have a predominantly cutaneous component wound healing and in the growth of tumours. Endothelial cells are also
while others are predominantly muscular. Each consists of arteriosomes active participants in, and regulators of, inflammatory processes (Pober
and venosomes linked to neighbouring angiosomes by either similar and Sessa 2007).


calibre (true) or reduced calibre (choke) anastomoses. Anastomoses Although endothelial cells are thin, they extend over a relatively large
between adjacent angiosomes may occur within the skin or within surface area. They are thickest at the nucleus, where they can reach
muscle. Some muscles are supplied by a single artery and its accompa- 2–3 µm, causing a slight bulge into the lumen (see Fig. 6.10). Else-
nying veins and therefore lie within one angiosome, while other muscles where, they are thin and laminar, and are often as little as 0.2 µm thick
are supplied by more than one vessel and therefore cross more than in capillaries. They are generally elongated in the direction of blood
one angiosome. A detailed knowledge of anatomical vascular territories flow, especially in arteries (see Fig. 6.17).
and spatial angiosome architecture is essential in designing, evaluating Except in sinusoids, endothelial cells usually adhere to each other at
and raising axial flaps based on vascular connections in plastic and their edges, so there is no discontinuity in the lining of the lumen. They
reconstructive surgery. adhere to adjacent cells through the junctional complex, an area of
apposition where adherent and tight junctions are found. They also
communicate via gap junctions, which are most marked in continuous
MICROSTRUCTURE OF BLOOD VESSELS
capillaries. Cell contacts and myoendothelial gap junctions between
endothelial and smooth muscle cells are common in small resistance
Intima
arteries and arterioles, where the separation between endothelium and
media is reduced and the inner elastic lamina is either very thin or
The intimal lining of blood vessels consists of an endothelium, and a absent. Myoendothelial gap junctions play an important role in the
variable amount of subendothelial connective tissue, depending on the integration and regulation of vascular function (Figueroa and Duling
vessel. 2009).
Transcytotic (pinocytotic) vesicles (see Fig. 6.11) are present in all
Endothelium
endothelial cells but are particularly numerous in exchange vessels; they


The endothelium is a monolayer of flattened polygonal cells that include caveolae (see Fig. 6.4) typical of smooth muscle cells. They
extends continuously over the luminal surface of the entire vascular tree shuttle small amounts of interstitial fluid or plasma across the endothe-
(see Fig. 6.10; Fig. 6.17). Its structure varies in different regions of the lial cytoplasm and thus facilitate bulk exchange of nutrients and metab-
vascular bed. olites between these compartments. They are normally the only means
The endothelium is a key component of the vessel wall and sub- by which protein can cross the endothelium. Endothelial cells secrete
serves several major physiological roles. Endothelial cells are in contact many factors but they do not have the morphological characteristics of
with the blood stream and thus influence blood flow. They regulate the secretory cells.
diffusion of substances and migration of cells out of and into the cir- The Wiebel–Palade body is characteristic of endothelial cells. It is an
culating blood. In the brain, endothelial cells of small vessels actively elongated cytoplasmic vesicle, 0.2 × 2–3 µm in length, which contains
transport substances, e.g. glucose, into the brain parenchyma. Endothe- regularly spaced tubular structures parallel to its long axis. Wiebel–
lial cells play an important role in haemostasis because they produce Palade bodies play a role in both inflammation and haemostasis
von Willebrand factor, which promotes platelet adhesion (see below); because they store the adhesion molecule P-selectin (see below) and
secrete prostacyclin and thrombomodulin, which limits clot formation; von Willebrand factor, which mediates platelet adhesion to the extracel-
and promote fibrinolysis by secreting tissue plasminogen activator. lular matrix after vascular injury.
They have selective phagocytic activity and are able to extract substances
from the blood. For example, the endothelium of pulmonary vessels von Willebrand factor
removes and inactivates several polypeptides, biogenic amines, brady- Von Willebrand factor (vWF) is a very large, multimeric glycoprotein
kinin, prostaglandins and lipids from the circulation, and converts the consisting of at least 80 monomers of 250 kDa each, responsible for


precursor of angiotensin II to its active form. the characteristic appearance of Wiebel–Palade bodies. Its function is
Endothelial cells secrete vasoconstrictor (thromboxane) and vasodi- to bind to other proteins and provide a bridge between them.
lator (prostacyclin) prostaglandins, nitric oxide (NO) and endothelin
(a vasoconstrictor). They respond to stretch (e.g. increased pressure) Endothelial cell–leukocyte interactions
and the shear effect of blood flow via stretch-sensitive ion channels in The luminal surface of endothelial cells does not normally support the
the cell membrane. Endothelial cells synthesize components of the adherence of leukocytes or platelets. However, many functions of
basal lamina. They proliferate to provide new cells during growth of human vascular endothelial cells are dynamic rather than fixed. Acti-
blood vessels, to replace damaged endothelium, and to provide solid vated endothelial cells and the characteristic endothelium of high
cords of cells that develop into new blood vessels (angiogenesis). endothelial venules (HEVs) of lymphoid tissues are sites of leukocyte
Angiogenesis, which may be stimulated by endothelial production of attachment and diapedesis (see below).


Smooth muscle and the cardiovascular and lymphatic systems
132.e1
6
RETPAHC
On release from endothelial cells, vWF binds to collagen in the
subendothelial matrix; when this is exposed following vascular damage,
vWF facilitates platelet adhesion by binding to platelet glycoprotein
receptors. This is particularly efficient in high-flow/shear-stress condi-
tions, when it also causes platelet activation. Although the major source
of vWF is probably endothelial cells, it is also produced by megakaryo-
cytes and stored in platelet α-granules. vWF is present in plasma, where
it binds and stabilizes factor VIII, a clotting protein secreted into the
blood stream by hepatocytes. Hereditary deficiency or defective func-
tion of vWF causes defective haemostasis and a tendency to bleed (von
Willebrand disease) (reviewed in Sadler (2005)).


Cardiovascular and lymphatic systems
133
6
RETPAHC
HEVs (Fig. 6.18) are located within the T-cell domains, between and integrins are expressed on leukocytes and mediate adhesion of circulat-
around lymphoid follicles in all secondary lymphoid organs and tissues ing cells to the endothelium, which expresses selectins and members of
except the spleen. They are specialized venules of 7–30 µm diameter, the immunoglobulin supergene family. Regulated expression of these
which possess a conspicuous cuboidal endothelial lining. The luminal molecules by both cell types provides the means by which leukocytes
aspect of HEVs shows a cobblestone appearance. The endothelial cells recognize the vessel wall (leukocyte homing antigens and vascular
rest on a basal lamina and are supported by pericytes and a small addressins), adhere to it and subsequently leave the circulation.
amount of connective tissue (Fig. 6.19). They are linked by discontinu- The first step in this cascade is the loose binding or tethering of
ous adhesive junctions at their apical and basal aspects; the junctions leukocytes, and this is initiated via L-, P- or E-selectin. This weak, revers-
are circumnavigated by migrating lymphocytes. Ultrastructurally, the ible adhesion allows leukocytes to roll along the endothelial surface of
endothelial cells have the characteristics of metabolically active secre- a vessel lumen at low velocity, making and breaking contact, and sam-
tory cells. Thus they contain large, rounded, euchromatic nuclei with pling the endothelial cell surfaces. Recognition of chemokines (chemo-
one or two nucleoli, prominent Golgi complexes, many mitochondria, tactic signalling molecules) presented by the endothelium leads to
ribosomes and pinocytotic vesicles. Typically, they also possess Wiebel– ‘inside-out’ signalling and conversion of integrins at the leukocyte
Palade bodies (see above). surface into actively adhesive configurations that bind strongly to their
Many of the adhesion molecules that mediate interactions between endothelial ligands, resulting in stable arrest. Finally, the leukocyte
blood leukocytes and HEVs or cytokine-activated endothelium have migrates through the vessel wall (diapedesis), passing either between


been identified. They can be divided into three general families: selectins, (paracellular migration) or across (transcellular migration) endothelial
integrins and the immunoglobulin supergene family. Selectins and cells. Transcellular migration is thought to be the preferred pathway;
endothelial transcytotic vesicles (caveolae), intermediate filaments
(vimentin) and F-actin are important in the creation of transient trans-
cellular channels through which leukocytes pass. They then cross the
basal lamina and migrate into the surrounding tissue by mechanisms
that involve CD31 antigen and matrix metalloproteinases (reviewed in
Vestweber (2007)).
Cell adhesion molecules
There are three known members of the selectin family of adhesive
proteins: L-selectin (also known as lymphocyte homing receptor),
E-selectin and P-selectin. L-selectin is expressed on most leukocytes.
Endothelial cells of HEVs in lymphoid organs express its oligosaccha-
ride ligand, although other molecules such as mucins may be alterna-
tive ligands. L-selectin mediates homing of lymphocytes, especially to
peripheral lymph nodes, but also promotes the accumulation of neu-
trophils and monocytes at sites of inflammation. E-selectin is an induc-
ible adhesion molecule that mediates adhesion of leukocytes to
inflammatory cytokine-activated endothelium, and is only transiently
expressed on endothelium. P-selectin is rapidly mobilized from Wiebel–
Palade bodies, where it is stored, to the endothelial surface after
Fig. 6.18 A high endothelial venule in a human lymph node, sectioned endothelial activation. It binds to ligands expressed on neutrophils,
longitudinally, lined by cuboidal endothelium (arrow). Erythrocytes and platelets and monocytes, and, like E-selectin, tethers leukocytes to
leukocytes (mainly lymphocytes and neutrophils) are seen in the lumen. endothelium at sites of inflammation. P-selectin is quickly endocytosed
(Courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, by the endothelial cells and so its expression is short-lived.
Department of Histopathology, Royal Cornwall Hospitals Trust, UK.)
The integrins are a large family of molecules that mediate cell-to-cell


adhesion as well as interactions of cells with extracellular matrix.
Certain β integrin heterodimers are expressed on lymphocytes 2–4
1
weeks after antigenic stimulation (very late antigens, VLAs) and bind to
the extracellular matrix. Additionally, VLA-4, present on resting lym-
phocytes (expression increases after activation), monocytes and eosi-
nophils, binds to the vascular cell adhesion molecule-1 (VCAM-1), the
ligand on activated endothelium. In contrast to β integrins, which
1
many cells express, the expression of β integrins is limited to white
2
blood cells. Although the leukocyte integrins are not constitutively
adhesive, they become highly adhesive after cell activation and there-
fore play a key role in the events required for cell migration. The
endothelial ligands for one such β integrin are the intercellular adhe-
2
sion molecules-1 and 2 (ICAM-1 and ICAM-2), which belong to the
immunoglobulin superfamily.
Three members of the large immunoglobulin superfamily of pro-
teins are involved in leukocyte–endothelial adhesion, providing integrin
N
counter-receptors on the endothelial cell membrane. ICAM-1 and
ICAM-2 are constitutively expressed but upregulated by inflammatory
cytokines. VCAM-1 is absent from resting endothelium but is induced
by cytokines on activated endothelium and promotes extravasation of
EC lymphocytes at sites of inflammation.
Subendothelial connective tissue
L The subendothelial connective tissue, also termed the lamina propria,
is a thin but variable layer. It is largely absent in the smallest vessels,
where the endothelium is supported instead by pericytes (see Fig. 6.21).
It contains a typical fibrocollagenous extracellular matrix, a few fibro-
L
blasts and occasional smooth muscle cells. Endothelial von Willebrand
factor concentrates in this layer and participates in haemostasis and
platelet adhesion when the overlying endothelium is damaged.
Fig. 6.19 A high endothelial venule in transverse section in a human
Media
palatine tonsil. The lumen is completely filled by a neutrophil (N). Cuboidal


endothelial cells (EC) line the vessel. Two lymphocytes (L) with
heterochromatic nuclei are seen below, in transit within the wall of the The media consists chiefly of concentric layers of circumferentially or
vessel. (Courtesy of Dr Marta Perry, Department of Anatomy, St Thomas’s helically arranged smooth muscle cells with variable amounts of elastin
Hospital Medical School, London.) and collagen.


SmooTH muSClE And THE CARdiovASCulAR And lymPHATiC SySTEmS
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noiTCES
Smooth muscle
Smooth muscle forms most of the media of arteries (see Fig. 6.7) and
arterioles. A thinner layer of smooth muscle is also found in venules
and veins; small segments of the pulmonary veins nearest to the heart
contain striated cardiac muscle. Contraction of the smooth muscle in
arteries and arterioles reduces the calibre of the vessel lumen, reducing
IEL
blood flow through the vessel. This is particularly effective in small
resistance vessels, where the wall is thick relative to the diameter of the
vessel. Smooth muscle activation also increases the rigidity of the vessel
wall, reducing its compliance. In arteries this affects propagation of the
pulse, whereas in veins it effectively reduces their capacity.
The smooth muscle cells synthesize and secrete elastin, collagen and
other extracellular components of the media, which bear directly on
the mechanical properties of the vessels. The mechanics of the muscu-
lature of the media are complex. Distensibility, strength, self-support,
elasticity, rigidity, concentric constriction, etc. are interrelated functions
and are finely balanced in the different regions of the vascular bed.
In large arteries, where the blood pressure is high, the muscle cells
are shorter (60–200 µm) and smaller in volume than in visceral muscle.
In arterioles and veins, smooth muscle cells more closely resemble those
from the viscera. The cells are packed with myofilaments and other Fig. 6.20 The wall of a human muscular artery, stained for elastin (black),
elements of the cytoskeleton, including intermediate filaments. Vascular showing the internal elastic lamina (IEL). Fine, incomplete elastic lamellae
muscle cells contain intermediate filaments of either vimentin alone or are interspersed between smooth muscle cells of the tunica media. The
both vimentin and desmin, whereas the intermediate filaments of vis- endothelium is partly detached in this postmortem specimen. van Gieson
ceral smooth muscle are exclusively of desmin. Intercellular junctions stain.
are mainly of the adhesive (adherens) type, coupling cells mechanically.
Gap junctions couple cells electrically and allow passage of small signal-


ling molecules. Junctions between muscle cells and the connective tissue transmit force around the circumference of the vessel. In a distended
matrix are particularly numerous, especially in arteries. vessel, the elastic fibres store energy and, by recoiling, help to restore
The muscle cells of the arterial media can be regarded as multifunc- the resting length and calibre.
tional mesenchymal cells. After damage to the endothelium, muscle The extracellular material of the media, including collagen and
cells migrate into the intima and proliferate, forming bundles of longi- elastin, is produced by the muscle cells. Its turnover is slow compared
tudinally orientated cells that reform the layer. In certain pathological to that in other tissues. In the adventitia, collagen is synthesized and
conditions, muscle cells (and macrophages) undergo fatty degeneration secreted by fibroblasts, as in other connective tissues. During postnatal
and participate in the formation of atheromatous plaques. development, while vessels increase in diameter and wall thickness,
there is an increase in elastin and collagen content. Subsequent changes
in vessel structure, seen during ageing, include an increase in the ratio
Collagen and elastin
of collagen to elastin, with a reduction in vessel elasticity.
Components of the extracellular matrix (see Ch. 2) are major constitu-
ents of vessel walls; in large arteries and veins they make up more than Adventitia
half of the mass of the wall, mainly in the form of collagen and elastin.
Other fibrous components such as fibronectin, and amorphous prote-
The adventitia is formed of general connective tissue, varying in the
oglycans and glycosaminoglycans, are present in the interstitial space.
thickness and density of its collagen fibre bundles.
Elastin is found in all arteries and veins and is especially abundant
in elastic arteries (see Fig. 6.6). Individual elastic fibres (0.1–1.0 µm in Vasa vasorum
diameter) anastomose with each other to form net-like structures, In smaller vessels, the nourishment of the tissues of the vessel wall is
which extend predominantly in a circumferential direction. More exten- provided by diffusion from the blood circulating in the vessel itself. The
sive fusion produces lamellae of elastic material, which, though usually wall thickness at which simple diffusion from the lumen becomes


perforated and thus incomplete, separate the layers of muscle cells. The insufficient is 1 mm. Large vessels have their own vascular supply
internal elastic lamina is a conspicuous elastic lamella in arteries, within the adventitia (see Fig. 6.8), in the form of a network of small
between intima and media, which allows the vessel to recoil after dis- vessels, the vasa vasorum. These originate from, and drain into, periph-
tension. When the intraluminal pressure falls below physiological eral branches of the vessel they supply. They ramify within the adven-
limits (post mortem), it is compressed and coils up into a regular cor- titia and, in the largest of arteries, penetrate the outermost part of the
rugated shape (Fig. 6.20; see Figs 6.7, 6.10), reducing but not obliterat- media. The vasa vasorum of the pulmonary artery arise from adjacent
ing the lumen; the profile of the artery remains circular. Fenestrations systemic arteries. The larger veins are also supplied by vasa vasorum but
in the elastic lamina, which may also be split in thickness, allow materi- these may penetrate the wall more deeply, perhaps because of the lower
als to diffuse between intima and media. An outer elastic lamina, oxygen tension.
similar in appearance to, but markedly less well developed and less
compact than, the internal elastic lamina, lies at the outer aspect of the Nervi vasorum
media at its boundary with the adventitia (see Fig. 6.7). These laminae Blood vessels are innervated by efferent autonomic fibres that regulate
are less evident in elastic arteries, where elastic fibres occupy much of the state of contraction of the musculature (muscular tone) and thus
the media (see Fig. 6.6). the diameter of the vessels, particularly the resistance arteries and arte-
Collagen fibrils are found in all three vessel layers. Type III collagen rioles. Perivascular nerves branch and anastomose within the adventitia
(reticulin) occupies much of the interstitial space between the muscle of an artery, forming a meshwork around it. Nerves are occasionally
cells of the media and is also found in the intima. Collagen is abundant found within the outermost layers of the media in some of the large


in the adventitia, where type I collagen fibres form large bundles that muscular arteries.
increase in size from the junction with the media to the outer limit of Nervi vasorum are small bundles of axons, which are almost invari-
the vessel wall. In veins, collagen is the main component of the vessel ably unmyelinated and typically varicose. Most are postganglionic
wall and accounts for more than half its mass. axons derived from neurones in sympathetic ganglia. The density of
In general terms, collagen and elastic fibres in the media run parallel innervation varies in different vessels and in different areas of the body;
to, or at a small angle to, the axes of the muscle cells, and they are it is usually sparser in veins and larger lymphatic vessels. Large veins
therefore arranged mainly circumferentially. In contrast, the predomi- with a pronounced muscle layer, such as the hepatic portal vein, are
nant arrangement of collagen fibres in the adventitia is longitudinal. well innervated. Some vessels in the brain may be innervated by intrin-
This arrangement imposes constraints on length change in large vessels sic cerebral neurones, although neural control of brain vessels is of
under pressure, e.g. in large arteries, in which the radial distension minor importance compared with metabolic and autoregulation (local
under the effect of the pulse far exceeds the longitudinal distension. response to stretch stimuli).
The outer sheath of type I collagen in the adventitia therefore has a The control of vascular smooth muscle is complex. Vasoconstrictor
structurally supportive role. The more delicate type III collagen network adrenergic fibres release noradrenaline (norepinephrine), which acts
of the media provides attachment to the muscle cells and its role is to on α-adrenergic receptors in the muscle cell membrane. In addition,


Cardiovascular and lymphatic systems
135
6
RETPAHC
circulating hormones and factors such as nitric oxide, prostaglandins Cerebral capillaries are the site of the blood–brain barrier. They are
and endothelin, which are released from endothelial cells, exert a pow- lined by endothelial cells, which are joined by tight junctions. The
erful effect on the muscle cells. Neurotransmitters reach the muscle endothelial cytoplasm contains a few pinocytotic vesicles. The cells are
from the adventitial surface of the media, whereas hormonal and surrounded by a basal lamina (see Fig. 3.12); at points of contact with
endothelial factors diffuse from the intimal surface. In a few tissues, perivascular astrocytes, the intervening basal lamina is formed by fusion
sympathetic cholinergic fibres inhibit smooth muscle contraction and of the endothelial and glial basal laminae. Pericytes, completely sur-
induce vasodilation. Vascular smooth muscle exhibits endogenous rounded by basal lamina, are present around capillaries. Perivascular
(myogenic) activity in response to stretch and shear. macrophages are attached to the outer walls of capillaries and to other
Most arteries are accompanied by nerves that travel in parallel with vessels; they are phenotypically distinct from parenchymal microglia,
them to the peripheral organs that they supply. However, these paravas- which are also of monocytic origin. A thin layer of meningeal cells
cular nerves are quite independent and do not innervate the vessels they derived from the pia mater surrounds arterioles but disappears at the
accompany. level of capillaries. For further descriptions of cerebral vessels, see
Chapter 19.
Pericytes
LYMPHATIC VESSELS
Pericytes are present at the outer surface of capillaries and the smallest
venules (postcapillary venules), where an adventitia is absent and there
Lymphatic capillaries form wide-meshed plexuses in the extracellular
are no muscle cells. They are elongated cells, whose long cytoplasmic
matrices of most tissues. They begin as dilated, blind-ended tubes with
processes are wrapped around the endothelium. Pericytes are scattered
larger diameters and less regular cross-sectional appearances than those


in a discontinuous layer around the outer circumference of capillaries.
of blood capillaries. Their basal laminae are incomplete or absent and
They are generally absent from fenestrated capillaries but form a more
they lack associated pericytes. The smaller lymphatic vessels are lined
continuous layer around postcapillary venules (Fig. 6.21). They are
by endothelial cells, which have numerous transcytotic vesicles within
gradually replaced by smooth muscle cells as vessels converge and
their cytoplasm and so resemble blood capillaries. However, unlike
increase in diameter.
capillaries, their endothelium is generally quite permeable to much
Pericytes are enclosed by their own basal lamina, which merges in
larger molecules: they are readily permeable to large colloidal proteins
places with that of the endothelium. Most display areas of close apposi-
and particulate material such as cell debris and microorganisms, and
tion with endothelial cells, and occasionally form adherens junctions
also to cells. Permeability is facilitated by gaps between the endothelial
where their basal laminae are absent. Pericyte cytoplasm contains actin,
cells, which lack tight junctions (discontinuous endothelium), and by
myosin, tropomyosin and desmin, which suggests that they are capable
pinocytosis. The lymphatic system provides an important transport
of contractile activity. They also have the potential to act as mesenchy-
pathway for leukocytes and defence against infection (reviewed in Saha-
mal stem cells, and participate in repair processes by proliferating and
rinen et al (2004)).
giving rise to new blood vessel and connective tissue cells. Pericytes, or
Lymph is formed from interstitial fluid, which is derived from blood
closely related cells, may be the source of myofibroblasts that contribute
plasma via filtration in the microcirculation. Much of the filtered fluid
to fibrosis in disease processes (reviewed in Duffield (2012)).
is reabsorbed by the time the blood leaves the venules, but about 15%
or 8 litres per day enters the lymphatics. Lymphatic vessels take up this
Cerebral vessels
residual fluid by passive diffusion and the transient negative pressures
in their lumina, which are generated intrinsically by contractile activity


Major branches of cerebral arteries that lie in the subarachnoid space of smooth muscle in the largest lymphatic vessel walls, and extrinsically
over the surface of the brain have a thin outer coating of meningeal by compression of the lymph vessels as a result of contraction of adja-
cells, usually one layer thick, where adjacent meningeal cells are joined cent muscle or arterial pulsation. The unidirectional flow of lymph is
by desmosomes and gap junctions. These arteries have a smooth muscle maintained by the presence of valves in the larger vessels (Fig. 6.22).
media and a distinct elastic lamina. Veins on the surface of the brain Lymphatic capillaries are prevented from collapsing by anchoring fila-
have very thin walls, and the smooth muscle layers in the wall are ments, which tether their walls to surrounding connective tissue struc-
often discontinuous. They are coated externally by a monolayer of tures and exert radial traction.
meningeal cells. In most tissues, lymph is clear and colourless; in the lymphatic capil-
As arteries enter the subpial space and penetrate the brain, they lose laries it has an identical composition to interstitial fluid. In contrast,
their elastic laminae, and consequently the cerebral cortex and white lymph from the small intestine is dense and milky, reflecting the pres-
matter typically contain only arterioles, venules and capillaries. The ence of lipid droplets (chylomicrons) derived from fat absorbed by the
exceptions are the large penetrating vessels in the basal ganglia, where mucosal epithelium. The terminal lymphatic vessels in the mucosa of
many arteries retain their elastic laminae and thick smooth muscle the small intestine are known as lacteals and the lymph as chyle. Lym-
media. Enlarged perivascular spaces form around these large arteries in phatic capillaries are not ubiquitous: they are not present in cornea,
ageing individuals. Arterioles and venules in the cortex and white cartilage, thymus, the central or peripheral nervous system or bone
matter can be distinguished from each other because arterioles are sur- marrow, and there are very few in the endomysium of skeletal muscles.
rounded by a smooth muscle coat, whereas veins and venules have Lymphatic capillaries join into larger vessels that pass to local lymph


larger lumina and thinner walls. nodes. Typically, lymph percolates through a series of nodes before
A
P
P
V
C L Ven
P
Fig. 6.22 A valve (V) in a lymphatic vessel (L), accompanying a small
Fig. 6.21 A scanning electron micrograph of capillary (C) and pericytes venule (Ven) and arteriole (A) in human connective tissue. (Courtesy of Mr
(P) supporting the vessel wall. (Courtesy of T. Fujiwara and Y. Uehara, Peter Helliwell and the late Dr Joseph Mathew, Department of
Department of Anatomy, Ehime University School of Medicine, Japan.) Histopathology, Royal Cornwall Hospitals Trust, UK.)


SmooTH muSClE And THE CARdiovASCulAR And lymPHATiC SySTEmS
136
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noiTCES
reaching a major collecting duct. There are exceptions to this arrange-
ment: the lymph vessels of the thyroid gland and oesophagus, and of
the coronary and triangular ligaments of the liver, all drain directly to
the thoracic duct without passing through lymph nodes. In the larger
vessels, a thin external connective tissue coat supports the endothelium.
The largest lymphatic vessels (200 µm) have three layers, like small
veins, although their lumen is considerably larger than that of veins
with a similar wall thickness. The tunica media contains smooth muscle
D
cells, mostly arranged circumferentially. Elastic fibres are sparse in
the tunica intima, but form an external elastic lamina in the tunica
adventitia.
The larger lymphatic vessels differ from small veins in having many
more valves (see Fig. 6.22). The valves are semilunar, generally paired
D
and composed of an extension of the intima. Their edges point in the
direction of the current, and the vessel wall downstream is expanded
into a sinus, which gives the vessels a beaded appearance when they are
distended. Valves are important in preventing the backflow of lymph.
Deep lymphatic vessels usually accompany arteries or veins, and
almost all reach either the thoracic duct or the right lymphatic duct,
E
which usually joins the left or right brachiocephalic veins respectively
at the root of the neck.
The thoracic duct is structurally similar to a medium-sized vein but
the smooth muscle in its tunica media is more prominent. Most lym- Fig. 6.23 Cardiac muscle fibres in human myocardium, sectioned
phatic vessels anastomose freely. Larger vessels have their own plexi- longitudinally. Cell branching and fine cross-striations are clearly visible
form vasa vasorum and accompanying nerve fibres. If their walls are and indicate the intracellular organization of sarcomeres. The dark
acutely infected (lymphangitis) this vascular plexus becomes congested, transverse lines are intercalated discs (D). Endomysium (E) contains nuclei
marking the paths of superficial vessels by red lines that are visible of endothelial cells and fibroblasts.


through the skin and tender to the touch.
Lymphatic vessels repair easily. New vessels form readily after
damage, beginning as solid cellular sprouts from the endothelial cells
Dyad Myofibril
of persisting vessels that subsequently become canalized.
Lymphoedema
Insufficient lymphatic drainage leads to accumulation of fluid in the
tissues (oedema) and swelling, typically in the limbs.
Sarcoplasmic
reticulum
CARDIAC MUSCLE
Terminal cisterna
T-tubule
of sarcoplasmic
In cardiac muscle, as in skeletal muscle, the contractile proteins are reticulum
organized structurally into sarcomeres that are aligned in register across
the fibres, producing fine cross-striations that are visible in the light
microscope. Both types of muscle contain the same contractile proteins
(although commonly different isoforms), which are assembled in a
similar way. The molecular basis for contraction, but not its regulation,
is the same. Elevation of cytosolic calcium triggers contraction, corre-
sponding to cardiac systole and the pumping phase of the heart cycle.
Removal of cytosolic calcium induces relaxation, corresponding to dias-
tole and cardiac filling. Despite the similarities, there are major func-
tional, morphological and developmental differences between cardiac
and skeletal muscle.
MICROSTRUCTURE OF CARDIAC MUSCLE
The myocardium, the muscular component of the heart, constitutes the
bulk of its tissues. It consists predominantly of cardiac muscle cells,
which are usually 120 µm long and 20–30 µm in diameter in a normal
adult. Each cell has one or two large nuclei occupying the central part
of the cell, whereas skeletal muscle has multiple, peripherally placed
nuclei. The cells are branched at their ends, and the branches of adjacent
cells are so tightly associated that their appearance under light micros-
copy is of a network of branching and anastomosing fibres (Fig. 6.23).
Cells are bound together by elaborate junctional complexes, the inter-
calated discs (Fig. 6.24; see Figs 6.23, 6.26).
Fine fibrocollagenous connective tissue is found between cardiac
muscle fibres. Although this is equivalent to the endomysium of skeletal
muscle, it is less regularly organized because of the complex three-
dimensional geometry imposed by the branching cardiac cells. Numer-


ous capillaries and some nerve fibres are found within this layer. Coarser
Gap junction
connective tissue, equivalent to the perimysium of skeletal muscle,
Z-disc
separates the larger bundles of muscle fibres, and is particularly well Sarcomere
developed near the condensations of dense fibrous connective tissue Fascia adherens Sarcolemma
that form the ‘skeleton’ of the heart. The ventricles of the heart are Fig. 6.24 A three-dimensional reconstruction of cardiac muscle cells in
composed of spiralling layers of fibres that run in different directions. the region of an intercalated disc, a junctional complex between
Consequently, microscope sections of ventricular muscle inevitably neighbouring cells. The interdigitating transverse parts of the intercalated
contain the profiles of cells cut in a variety of orientations. A linear disc form a fascia adherens, with numerous desmosomes; gap junctions
arrangement of cardiac muscle fibres is found only in the papillary are found in the longitudinal parts of the disc. The organization of the
muscles and trabeculae carneae. transverse tubules and sarcoplasmic reticulum is also shown.


Smooth muscle and the cardiovascular and lymphatic systems
136.e1
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In the developed world, secondary lymphoedema is most com-
monly the consequence of treatment for cancer, particularly breast
cancer, following either surgical removal of lymph nodes and vessels,
or their damage by radiation therapy. Tumours can themselves cause
lymphoedema if they compress and block lymph vessels. Lymph node
infections can also restrict lymph flow. In tropical regions, invasion of
the lymphatic vessels by thread-like nematode worms (filariasis) can
lead to severe swelling, particularly in the legs and genitals (elephan-
tiasis) (Pfarr et al 2009). Podoconiosis is a non-filarial elephantiasis
endemic to tropical highland areas of Africa and elsewhere. It is thought
to be due to an abnormal inflammatory reaction to volcanic red clay
soils (Fuller 2005). Both filariasis and podoconiosis have a large socio-
economic impact. Primary lymphoedema is a rare inherited condition,
most common in females, and may involve abnormal development of
lymph nodes or valves in the lymphatic vessels.


Cardiac muscle
137
6
RETPAHC
Electron micrographs of cardiac muscle cells in longitudinal section The sarcolemma of ventricular cardiac muscle cells invaginates to
show that the myofibrils separate before they pass around the nucleus, form T-tubules with a wider lumen than those of skeletal muscle; atrial
leaving a zone that is occupied by organelles, including sarcoplasmic muscle cells have few or no T-tubules. Unlike skeletal muscle, most
reticulum, Golgi complex, mitochondria, lipid droplets and glycogen T-tubules penetrate the sarcoplasm at the level of the Z-discs (see Fig.
(Fig. 6.25). At the light microscopic level, these zones appear in longi- 6.24). The T-tubules are interconnected at intervals by longitudinal
tudinal sections as unstained areas at the poles of each nucleus. They branches to form a complex network. They serve a similar function in
often contain lipofuscin granules, which accumulate there in individu- skeletal and cardiac muscle, i.e. to carry the wave of depolarization into
als over the age of 10; the reddish-brown pigment may be visible even the cores of the cells.
in unstained longitudinal sections. The sarcoplasmic reticulum is a membrane-bound tubular plexus
The cross-striations of cardiac muscle are less conspicuous than that surrounds and defines, sometimes incompletely, the outlines of
those of skeletal muscle. This is because the contractile apparatus of individual myofibrils. Its main role, as in skeletal muscle, is the storage,
cardiac muscle lies within a mitochondria-rich sarcoplasm. The myofi- release and reaccumulation (sequestration) of calcium ions. The
brils are also less well delineated in cardiac muscle; in transverse sec- calcium-binding protein calsequestrin allows large amounts of calcium
tions they often fuse into a continuous array of myofilaments, irregularly to be stored within the sarcoplasmic reticulum and modulates activity
bounded by mitochondria and longitudinal elements of sarcoplasmic of the calcium release channels (ryanodine receptors) (Györke and
reticulum. The large mitochondria, with their closely spaced cristae, Terentyev 2008). The sarcoplasmic reticulum is separated from the


reflect the highly developed oxidative metabolism of cardiac tissue. The T-tubules by a 15 nm gap spanned by structures termed junctional
proportion of the cell volume occupied by mitochondria (approxi- processes, which are thought to be the cytoplasmic part of the calcium
mately 35%) is even greater in cardiac muscle than it is in slow twitch release channels; similar processes are found in skeletal muscle at the
skeletal muscle fibres. The high demand for oxygen is also reflected in junctional surface of the terminal cisternae. Sarcoplasmic reticulum
high levels of myoglobin and an exceptionally rich network of capillar- bearing junctional processes is termed junctional sarcoplasmic reticu-
ies around the fibres. lum to distinguish it from free sarcoplasmic reticulum, which forms a
The force of contraction is transferred through the ends of the cardiac longitudinal network. Junctional sarcoplasmic reticulum makes contact
muscle cells via the junctional strength provided by the intercalated with both the T-tubules and the sarcolemma (of which the T-tubules
discs. As in skeletal muscle, force is also transmitted laterally to the are an extension). Sarcoplasmic reticulum forms small globular exten-
sarcolemma and extracellular matrix via vinculin-containing elements sions (corbular sarcoplasmic reticulum) in the vicinity of the Z-discs,
that bridge between the Z-discs of peripheral myofibrils and the plasma but not in immediate relation to T-tubules or the sarcolemma. Since
membrane. The actin-binding proteins spectrin and dystrophin, impor- the junctions between T-tubules and sarcoplasmic reticulum usually
tant components of the cardiac muscle cell cytoskeleton, associate inde- involve only one structure of each type, the corresponding profiles in
pendently with the sarcolemma to provide mechanical support. Both electron micrographs are referred to as dyads, rather than triads as in
protein complexes form components of the costamere (Peter et al 2011; skeletal muscle.
Samarel 2005), which, in addition to transmitting force from sarcom-
eres to the sarcolemma and extracellular matrix, is central to mechani- Intercalated discs
cally generated signalling mechanisms.
Atrial muscle cells are smaller than ventricular cells. The cytoplasm


Intercalated discs are unique, complex junctions between cardiac myo-
near the Golgi complexes at the poles of the nuclei exhibits dense
cytes. In the light microscope they are seen as transverse lines crossing
membrane-bound granules that contain the precursor of atrial natri-
the tracts of cardiac cells (see Fig. 6.23). They may step irregularly
uretic peptide. This hormone promotes loss of sodium and water in the
within or between adjacent tracts, and may appear to jump to a new
kidneys, reducing blood volume and thereby lowering blood pressure.
position as the plane of focus is altered. Ultrastructurally, they are seen
It is released into the blood in response to stretch of the atrial wall.
to have transverse and lateral portions (see Fig. 6.24; Fig. 6.26). The
Atrial natriuretic peptide and aldosterone have antagonistic effects on
transverse portions occur wherever myofibrils abut the end of the cell,
renal sodium and water handling, via independent mechanisms.
and each takes the place of the last Z-disc. At this point, the actin fila-
ments of the terminal sarcomere insert into a dense subsarcolemmal
matrix that anchors them, together with other cytoplasmic elements
such as intermediate filaments, to the plasma membrane. Prominent
desmosomes, often with a dense line in the intercellular space, occur
at intervals along each transverse portion. This junctional region is
MMyy
FA
MM
Fig. 6.25 A low-power transmission electron micrograph of cardiac
muscle in longitudinal section, including the perinuclear zone of one of
the fibres. Note the abundant large mitochondria (M) between myofibrils Fig. 6.26 An intercalated disc in cardiac muscle, with several zones of
(My), and an intercalated disc (circled). (Courtesy of Professor Brenda electron-dense fascia adherens (FA) and a gap junction (arrow). (Courtesy
Russell, Department of Physiology and Biophysics, University of Illinois at of Professor Brenda Russell, Department of Physiology and Biophysics,
Chicago.) University of Illinois at Chicago.)


SmooTH muSClE And THE CARdiovASCulAR And lymPHATiC SySTEmS
138
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noiTCES
homologous with, and probably similar in composition to, the struc- influence on the pacemaker region, the sinuatrial (SA) node, whereas
ture found on the cytoplasmic face of the myotendinous junction, and activation of the left vagus slows propagation of the impulse mainly
is a type of fascia adherens junction. It provides firm adhesion between through its effect on the atrioventricular (AV) node. Vagal activity has
cells, and a route for the transmission of contractile force from one cell little direct effect on ventricular contractility.
to the next. Postganglionic sympathetic nerve fibres from the cervical sympa-
The lateral portions of an intercalated disc run parallel to the myo- thetic ganglia reach the heart via the recurrent cardiac nerves. Parasym-
filaments and the long axis of the cell, for a distance that corresponds pathetic fibres in the heart are derived from ganglion cells in the
to one or two sarcomeres before turning again to form another trans- cardiac plexuses and atrial walls that are innervated by preganglionic
verse portion. They are therefore responsible for the stepwise progres- cardiac branches of the vagus. Adrenergic, cholinergic and peptidergic
sion of the intercalated disc, which is seen microscopically. The lateral endings have been demonstrated in the myocardium. Fibres often end
portions contain gap junctions between adjacent cells (see Fig. 6.26), close to muscle cells and blood vessels, but junctional specializations
which provide electrical coupling and so enable the electrical impulse are not seen, and a gap of at least 100 nm remains between myocyte
to propagate from one cell to the next, spreading excitation and contrac- and axon. It is probable that neurotransmitters diffuse across this gap
tion rapidly along the branching tracts of interconnected cells. The to the adjacent cells. Some of the endings represent efferent nerve ter-
activity of the individual cells of the heart is thus coordinated so that minals, while others function as pain receptors, mechanoreceptors or
they function as if they were a syncytium. chemoreceptors.
Contractile protein isoforms
EXCITATION–CONTRACTION COUPLING


of cardiac muscle
IN CARDIAC MUSCLE
As in skeletal muscle, the contractile proteins of cardiac muscle exist in The molecular interaction between actin and myosin that underlies the
a number of tissue- and stage-specific forms. generation of force is initiated by elevation of cytosolic calcium in both
cardiac and skeletal muscle. However, there are significant differences
Endocardium in both the mechanisms by which this occurs and the physical arrange-
ment and molecular composition of the contractile elements (reviewed
The whole inner surface of the heart is covered by a thin layer of cells in Bers (2002)).
forming the endocardium, which separates the myocardium from the One of the major functional differences between cardiac and skeletal
blood. These cells are very similar to the endothelial cells that line muscle is the way in which contractile force is regulated. Smoothness
blood vessels, with a similar biological activity and embryological and gradation of contraction in skeletal muscle depend on recruitment
origin. They are now recognized as playing an important signalling role and asynchronous firing of different numbers of motor units. Individ-
in cardiac muscle function (reviewed in Brutsaert (2003)). ual motor units can also build up a contraction through a brief series
of re-excitations. In the heart, the entire mass of muscle must be
activated almost simultaneously, and mechanical summation by
NEUROVASCULAR SUPPLY OF CARDIAC MUSCLE re-excitation is not possible, because the cells are electrically refractory
until mechanical relaxation has taken place (see below).
Vascular supply As in skeletal muscle, cardiac muscle contraction is initiated when
calcium binds to troponin-C, a component of the regulatory protein
complex on the thin filaments. During basal activity of the heart, the
The activity of the heart is equivalent to a constant power expenditure
amount of calcium bound to troponin-C during each systole induces
of 1.3 watts under basal conditions, and escalates to 3 watts or more
less than half-maximal activation of the contractile apparatus. Contrac-
during physical exertion. Cardiac muscle cells contain glycogen, which
tile force can therefore be increased by increasing cytosolic calcium and
is a reserve during peaks of activity, but the majority of their energy
thus the amount bound to troponin-C. This is achieved by controlling
requirement is continuous and supplied only through a highly devel-


the amount of free calcium that is released into the cytosol during
oped oxidative metabolism, as is evident from the high proportion of
systole.
the cell volume that is occupied by mitochondria. This metabolism has
A special feature of the cardiac muscle cell is the long duration of
to be supported by a rich blood supply. Myocardium has a very high
its action potential. This is due to activation of voltage-dependent
perfusion rate of 0.5 ml/min/g of tissue (5 times that of liver and 15
L-type calcium channels in the sarcolemma by the initial depolariza-
times that of resting skeletal muscle). No cardiac muscle cell is more
tion, through which calcium enters the cell, sustaining the depolariza-
than 8 µm from a capillary, and vascular channels occupy a high pro-
tion and so causing a long-lasting electrical plateau of equivalent length
portion of the total interstitial space. Cardiac muscle is supplied by the
to the contraction. However, calcium influx during the plateau only
coronary vessels. Although there is some variation in the detailed dis-
accounts for about 25% of the elevation of cytosolic calcium; the rest
tribution of the arterial branches, the left ventricle, which has the
is released from the sarcoplasmic reticulum.
highest workload and largest mass, receives the highest arterial blood
Action potentials are conducted into the T-tubules, where they acti-
flow. Branches run in the myocardium along the coarser aggregations
vate L-type channels and calcium influx. This causes a localized increase
of connective tissue and ramify extensively in the endomysial layer,
in free calcium in the narrow space between the T-tubules and junc-
creating a rich plexus of anastomosing vessels. This plexus includes
tional sarcoplasmic reticulum, which activates calcium release channels
lymphatic as well as blood capillaries, which is not the case in skeletal
on the latter, causing calcium to flood out into the cytosol. This
muscle.
‘calcium-induced calcium release’ is a vital component of cardiac
The high oxygen requirement of the myocardium makes it vulner-
muscle activation and is the principal or only mechanism by which
able to ischaemic damage arising from atheroma or embolism in the


calcium can be released from the sarcoplasmic reticulum in the myo-
coronary arteries. This vulnerability is exacerbated in the left ventricle
cardium. This major difference between cardiac and skeletal muscle is
because embedded coronary arteries are compressed by contraction of
reflected in tissue-specific isoforms of calcium release channels.
the myocardium, limiting perfusion during systole. Arterial anastomo-
Systolic activation is terminated on repolarization of the action
ses, often more than 100 µm in diameter, are found throughout the
potential by reuptake (sequestration) of calcium from the cytosol back
heart and are an important factor in determining whether an adequate
into the sarcoplasmic reticulum. This is mediated by a high-affinity
collateral circulation may develop after a coronary occlusion.
sarco-endoplasmic reticulum calcium ATPase (SERCA), which rapidly
reduces cytosolic free calcium to resting levels. The activity of this
Innervation
ATPase controls the rate of decay of the calcium transient and is there-
fore a determinant of the rate of relaxation of the heart. The sarcoplas-
Although the impulse-generating and conducting system of the heart mic reticulum contains a cardiac form of calsequestrin, a homologue
establishes an endogenous rhythm, the rate and force of contraction are of the proteins found in skeletal and smooth muscle. This calcium-
under neural influence. Both divisions of the autonomic nervous system binding protein buffers the free calcium concentration inside the sarco-
supply unmyelinated postganglionic fibres to the heart. The innervation plasmic reticulum, allowing it to store considerable amounts of total
is derived bilaterally but it is functionally asymmetrical. Activation of calcium without increasing the gradient against which SERCA must
the left stellate ganglion (sympathetic) has little effect on heart rate but pump. It may also modulate the activity of the calcium release channels
increases ventricular contractility, whereas activation of the right stellate (Györke and Terentyev 2008).
ganglion influences both rate and contractility. Activation of the right Whilst SERCA therefore allows rapid relaxation of the myocardium,
vagus nerve (parasympathetic) slows heart rate mainly through its the calcium that entered the cell during the action potential must also


Smooth muscle and the cardiovascular and lymphatic systems
138.e1
6
RETPAHC
The cardiac isoform of α-actin is not identical to the skeletal muscle
form and is encoded by a different gene, although the two are so similar
as to be functionally interchangeable. Both skeletal and cardiac iso-
forms of sarcomeric actin are expressed in fetal ventricular muscle. The
mRNA for skeletal α-actin increases postnatally and exceeds that of
cardiac actin in the adult.
The myosin heavy chain of human cardiac muscle exists in two
isoforms, α and β, both of which are present in the fetal heart. The α-
form persists as the adult isoform in atrial muscle, whereas the β-form
(which is associated with a slower rate of contraction) predominates in
ventricular muscle. Interestingly, the β-form of myosin heavy chain in
cardiac muscle is identical to the isoform in slow twitch skeletal muscle.
This identity between cardiac and slow twitch skeletal protein isoforms
is true of several proteins, including ventricular myosin light chains and
cardiac troponin-C. Other proteins, such as troponin-I and T, exist in
cardiac-specific forms in the adult, although skeletal isoforms are
expressed in the fetus and neonate. The appearance of cardiac-specific
isoforms of troponin-I and T in the blood, following their release from
damaged cardiac cells, is now a standard diagnostic test for myocardial
infarction.