tgf- is a multi - functional cytokine and its signaling pathway contributes to a wide range of immunological and biological effects on various cell types and several diseases .
tgf- has regulatory functions in cell proliferation , differentiation , migration , and survival that affect multiple biological processes such as cell development , carcinogenesis , fibrosis , and wound healing , as well as immune responses ( 1 ) .
there is some controversy in the literature as to the precise functions of tgf- ; for example , in atherosclerosis , it is not clear whether tgf- is pro - atherogenic or anti - atherogenic .
the inhibition of tgf-1 activity induces pro - atherogenic changes in the vessel wall of atherosclerotic animal models ( 2 ) .
furthermore , the neutralization of tgf-1 leads to an inflammatory response of the vessel wall and provokes plaque instability ( 3 ) .
after the engagement of tgf- type i & ii receptors , the smad - dependent pathways are activated .
the biological effects that result depend on the types of smad complex involved in this signaling response ( 4 ) .
this process is modulated by other accessory receptors such as tgf- type iii receptor ( 5 ) .
although the expression of endoglin is increased in atherosclerotic lesions , the functional roles of endoglin in atherosclerosis have not been fully clarified .
this review aims to suggest a hypothetical role for endoglin in atherosclerosis on the basis of previous reports .
endoglin ( cd105 ) is a homodimer composed of two identical 95 kda disulfide - linked subunits , and it is known as a hypoxia - inducible transmembrane glycoprotein ( 6 ) .
it consists of three domains : a large extracellular domain , a transmembrane domain , and a short intracellular domain .
the extracellular domain contains an arg - gly - asp ( rgd ) tri - peptide , four n - linked glycosylation sites , and one o - linked glycosylation site ( 7 ) .
the intracellular domain includes several serine and threonine residues , some of which are phosphorylation sites ( 8) . the human endoglin gene , which is located on chromosome 9 , is composed of 15 exons .
endoglin homologues have been identified in mice and pigs ; the amino acid sequences of these homologues each have more than 70% identity with human endoglin and more than 69% homology with -glycan , another type iii tgf- receptor ( tgf-r ) ( 10 ) .
two isoforms of endoglin were reported , long - form endoglin and short - form endoglin , which differ in the length of their intracellular domains and the degree of phosphorylation .
long - form endoglin has 47 amino acids in its cytoplasmic tail , has a high degree of phosphorylation and is expressed predominantly in endothelial cells , whereas short - form endoglin has only 14 amino acids in its intracellular domain and has a low level of phosphorylation ( 6,11 ) .
a soluble form of endoglin has also been identified in the sera of both cancer patients and healthy persons .
soluble forms are generated by the cleavage of the extracellular domain of endoglin by membrane - type metalloprotease-14 ( mmp-14 ) , which may serve as a naturally occurring antagonist for tgf- signaling ( 12 ) .
mmp-14 cleaves endoglin at position 586 to release a soluble fragment representing almost the entire endoglin extracellular domain ( 13 ) .
endoglin is expressed by various cells found in the blood vessel wall , including endothelial cells , monocytes / macrophages , fibroblasts and vascular smooth muscle cells ( 14 ) .
endoglin is upregulated during wound healing and tumor vascularization and in inflammatory tissues and developing embryos .
endoglin expression in blood vessels is increased during hypoxia or following vascular injury . in hypoxic conditions ,
endoglin transcription is induced by the formation of a multiprotein complex with smad3/smad4 , stimulating protein 1 ( sp1 ) , and hypoxia - inducible factor-1 ( hif-1 ) ( 15 ) .
smad - dependent tgf- signaling also enhances endoglin expression whereas tnf- was reported to inhibit the expression of endoglin by endothelial cells ( 16,17 ) .
in contrast to these results , expression of the soluble form of endoglin was increased following treatment with tnf- and hydrogen peroxide , which are known as pro - atherogenic mediators ( 18 ) .
endoglin was originally identified as a non - signaling co - receptor for tgf- since it does not contain intrinsic kinase activity .
the main function of endoglin is thought to be the regulation of tgf- signaling via interactions with several proteins within the tgf- signaling pathway .
endoglin binds to both of the tgf-1 and tgf-3 isoforms , following which the cytosolic domain of endoglin can be targeted by serine and threonine kinases , leading to the formation of a functional receptor complex ( 19 ) .
indeed , endoglin is not a true receptor for tgf- , but it strongly modulates the phosphorylation levels of tgf-rii , activin receptor - like kinase ( alk)-1 , and alk-5 ( 20 ) .
the presence of endoglin can also modulate the downstream signaling by tgf-ri / tgf-rii complexes .
recent studies have demonstrated that endoglin functions in an interplay between two signaling pathways involving alk-1 and alk-5 , respectively , that have differential effects on target cells .
endoglin / alk-1/smad1/5 signaling stimulates the migration , proliferation , and tube formation of endothelial cells , resulting in angiogenesis ( 21 ) .
in contrast , the endoglin / alk-5/smad2 pathway inhibits the activity of endothelial cells and angiogenesis by inhibiting the proliferation , tube formation , and migration of endothelial cells ( 22 ) .
in addition , endoglin has inhibitory effects on smad3-dependent tgf- signaling , resulting in effects on endothelial cells opposite to those that result from smad2-dependent signaling ( 23 ) .
mutations in endoglin have been reported in hereditary hemorrhagic telangiectasia , a disease characterized by malformations of vascular structure ( 24 ) .
the long - form and short - form endoglin isoforms are both able to bind to their ligands and interact with alk-1 and alk-5 ; however , the two membrane - bound endoglin isoforms differ in their affinity for each receptor , level of phosphorylation , and capacity to regulate tgf--dependent responses ( 25 ) .
long - form endoglin has pro - angiogenic effects through induction of endogenous nitric oxide synthase ( enos ) expression , whereas short - form endoglin has anti - angiogenic effects .
signaling , is thought to be cleaved from the cell membrane and enter the systemic circulation , and may represent a useful candidate marker of endothelial injury , activation , inflammation , and senescence ( 12 ) .
endothelial dysfunction plays an important role in the development of atherosclerosis by inducing infiltration of inflammatory cells and a prothrombogenic state .
in addition , the migration and proliferation of smooth muscle cells , which are processes that affect the plaque stability , are crucial in the progression of advanced atherosclerotic lesions .
tgf- signaling results in inhibition of the proliferation and migration of smooth muscle cells , as well as endothelial cell regeneration ( 26 ) .
it was also reported that inhibition of tgf- signaling reduced collagen content and plaque stability in a mouse model of atherosclerosis ( 3 ) . in this model ,
therefore , as an accessory receptor for tgf- , endoglin expressed by endothelial cells and smooth muscle cells may play an important role in modifying the development of atherosclerosis via the regulation of tgf--induced atheroprotective effects .
although the expression of endoglin was very low in nonatherosclerotic aortas , the expression of endoglin by macrophages , smooth muscle cells and endothelial cells was increased in early atherosclerotic lesions ( 14 ) . in advanced atherosclerotic plaques , smooth muscle cells expressed high levels of endoglin , a parameter that was independent of smooth muscle cell morphology and leukocyte infiltration .
moreover , endoglin modulates the expression of genes that are known to be related to pro - angiogenic effects ( vegf , angiopoietin-1 , and angiopoeitin-2 ) or anti - angiogenic effects ( notch signaling , notch-3 , and dll4 ) , respectively ( 27,28 ) .
several studies have also reported that the concentration of soluble endoglin increased in the blood of patients with hypercholesterolemia and atherosclerosis ( 29 ) .
increased soluble endoglin levels could be related to endothelial damage or dysfunction ; furthermore , soluble endoglin is an indicator of cardiovascular damage in hypertension and diabetes - associated vascular pathologies ( 30 ) .
the circulating concentration of soluble endoglin was reported to increase at early stages of atherosclerosis due to damage of endothelial cells and then decrease in later stages of atherosclerosis , which suggests a potential role of soluble endoglin in acute heart failure ( 31 ) . as a decoy receptor
the expression levels of endoglin and soluble endoglin were higher in atherogenic lesions than in healthy arteries .
two isoforms of endoglin differentially transduce tgf- signaling by activation of different smad components , and thereby modulate the biological effects of tgf- signaling .
long - form endoglin shows atheroprotective effect by induction of enos expression , while short - form endoglin and soluble endoglin forms enhance atherogenesis via downregulation of enos expression and inhibition of tgf- signaling .
 endoglin ( also known as cd105 or tgf- type iii receptor ) is a co - receptor involved in tgf- signaling . in atherosclerosis , tgf- signaling is crucial in regulating disease progression owing to its anti - inflammatory effects as well as its inhibitory effects on smooth muscle cell proliferation and migration . 
 endoglin is a regulator of tgf- signaling , but its role in atherosclerosis has yet to be defined . 
 this review focuses on the roles of the various forms of endoglin in atherosclerosis . 
 the expression of the two isoforms of endoglin ( long - form and short - form ) is increased in atherosclerotic lesions , and the expression of the soluble forms of endoglin is upregulated in sera of patients with hypercholesterolemia and atherosclerosis . 
 interestingly , long - form endoglin shows an atheroprotective effect via the induction of enos expression , while short - form and soluble endoglin enhance atherogenesis by inhibiting enos expression and tgf- signaling . 
 this review summarizes evidence suggesting that the different forms of endoglin have distinct roles in atherosclerosis . 
INTRODUCTION
STRUCTURE AND EXPRESSION
FUNCTION
ENDOGLIN AND ATHEROSCLEROSIS
CONCLUSION