**3. Inflammation and anemia**

In dialysis patients, inflammation expressed by high levels of CRP is also associated with low blood hemoglobin and/or resistance to eritropoyesis-stimulating agents (Barany et al., 1997; Bradbury et al., 2009; Gunnel et al., 1999; Owen et al., 1998). This has been attributed to the inhibition of erythropoietin secretion by pro-inflammatory cytokines. Inflammation also contributes to anemia by inducing functional iron deficiency probably blocking the delivery of iron from the reticuloendothelial cells to the hemathopoietic cells. Cytokines may also induce ferritin synthesis directly or by increasing iron uptake into hepatocytes. The increase in ferritin synthesis by hepatocytes and reticuloendothelial cells underlies in the iron storage pool during inflammation. Thus, inflammation among patients with CKD can contribute to anemia and impaired response to erythropoietin. Erythropoietin resistance by itself has been associated with higher short-term mortality in CKD patients (López-Gómez et al., 2008).


**2. Nitric oxide and uteroplacental circulation**

The endothelial cells in the uteroplacental circulation play an important physiological role in the maintenance of vasodilation of placental vessels, since these are not innervated. These endothelial cells produce prostacyclin and nitric oxide, causing vasodilation and also preventing platelet aggregation and platelet adhesion to endothelial cells [19].

 Nitric oxide (NO) regulates implantation and trophoblastic invasion as well as embryonic development [20]. In addition, vascular tone in the placenta is controlled by several vasoactive mediators, with NO being the most important [21].

Nitric oxide participates at the onset of placental vasculogenesis. The onset of vasculogenesis requires the expression of vascular endothelial growth factor (VEGF), the mitogenic effects of which are mediated by nitric oxide. There is no well-established level of NO required for adequate placental angiogenesis. Elevated levels of NO may prevent angiogenesis, and its effect on cell survival and proliferation depends on its concentration [22].

NO has an important role in facilitating pregnancy-induced expansive remodeling in the uterine circulation, especially in the larger arteries [7].

The NO signaling has an important role in the expansive circumferential gestational remodeling of the uterine circulation. It provides an interesting link to the theory that preeclampsia results from elevated levels of sFlt-1, a soluble receptor for vascular endothelial growth factor and placenta growth factor, in preeclamptic women [23].

An excess of soluble receptor would reduce the availability of these ligands to the maternal vascular wall and fetal growth retardation. The sFlt-1, when infused in pregnant rats, promotes glomerular proteinuria and endotheliosis, characteristics of the preeclampsia picture [24].

 Since both placenta growth factor and vascular endothelial growth factor stimulate endothelial NO release, a reduction in their signaling would create a vasoconstrictor imbalance and increase peripheral resistance and blood pressure. Thus, a reduction in NO signaling also impacts vessel remodeling in a way that would further increase uterine vascular resistance. This effect on structure, combined with loss of function (vasodilation), would further mitigate the increases in uterine [7].

In addition to the decrease in the synthesis of nitric oxide in the uteroplacental circulation in preeclampsia, the endothelium-dependent relaxation in response to acetylcholine is impaired in preeclamptic arteries. Additionally, the increased plasma fibronectin levels in preeclampsia may reflect fibronectin which has been shed by injured endothelial cells. Furthermore, soluble circulating endothelial cell adhesion molecules such as soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), and sE-selectin are significantly increased in preeclampsia compared to normal pregnancies. This suggests that there is an altered and pathological endothelial phenotype in preeclampsia [25].

## **3. Animal models for the study of nitric oxide during pregnancy**

Animal models using rats or mice are very useful for the study of the pathogenesis, diagnosis, and treatment of preeclampsia. N-Nitro-L-arginine methyl

ester (L-NAME) is an inhibitor of NO synthase, and it has been shown to promote arterial hypertension in pregnant rats [26, 27].

 The administration of L-NAME in adult rats, in addition to causing hypertension [28], promotes cardiac and aortic tissue damage [29], proteinuria, and glomerular endotheliosis [30].

Several animals have already been used as models of experimental hypertension, such as rhesus monkeys, dogs, and sheep. Most of the experimental studies use rats and mice. In these animals, four categories of preeclampsia are produced: (i) animals with surgically induced reduced uteroplacental blood flow, (ii) animals with preclinical symptoms induced by drugs, (iii) genetic animal models, and (iv) animals with preexisting hypertension developing preeclampsia [31].

 Few studies address the effects of inhibition of nitric oxide on fetal development. Most of the work on this subject is from the 1990s. In pregnant rats, this nitric oxide synthesis inhibitor causes fetal growth restriction by a reduction in cellular proliferation due to induction of apoptosis [32], reducing the body weight and causing hemorrhagic necrosis of neonate's hind limbs [33, 34].

This suggests that L-NAME crosses the placental barrier and affects the fetal NO synthesis, leading to cell death in the limbs because the NO has a role in limb and digit developments [35]. Reactive oxygen species (ROS) formation by L-NAME induces hemorrhages, oxidative stress, and limb reduction defects [30].

The administration of L-arginine, the precursor of nitric oxide, in mice during gestation promoted an increase in fetal weight presumably due to the contribution of NO in improving fetal-maternal circulation by vasodilation and subsequently increased blood volume and viscosity in the fetal-maternal circulation [36].

## **4. Effects of inhibition of nitric oxide on fetal heart development in animal models**

 The first studies on the importance of nitric oxide in cardiac development go back to the beginning of the year 2000. The role of nitric oxide on fetal cardiovascular development is only partially known. In addition, in women who had preeclampsia, their children are at greater risk of developing cardiovascular disease later in life [37].

The nitric oxide probably contributes to the transformation of the epitheliummesenchyme in the areas of the endocardial cushion, myocardial survival and angiogenesis, and myocardial remodeling. Impaired production of NO in the heart leads to structural congenital abnormalities, resulting in heart failure and increased mortality [38].

Inhibition of nitric oxide during cardiac development is known to promote bicuspid aortic valve defects [39], congenital septal defects, and increase in cardiomyocyte apoptosis [40].

Apoptosis occurs in situations of cardiac remodeling during or after pathological processes and was observed in the myocardium of newborns from rats with hypertension induced by L-NAME. Thus, apoptosis can also occur in postnatal maturation of the heart and other tissues of the cardiovascular system, which need to adapt to the new hemodynamic role [41].

In newborns from L-NAME mothers, the most significant change in the myocardium involved the microvasculature. The wall/lumen ratio of arterioles was significantly higher in neonates of L-NAME and spontaneously hypertensive rats (SHR) than of normotensive mothers at 2 and 15 days postnatal [42].

It is possible that the myocardial vascular changes induced by the blockade of nitric oxide synthesis in rats are due to the activation of the local angiotensin

### *Maternal and Fetal Complications Due to Decreased Nitric Oxide Synthesis during Gestation DOI: http://dx.doi.org/10.5772/intechopen.85383*

I-converting enzyme (ACE). Takemoto et al. [43] found an increase in ACE in the coronary arteries and increase of the wall/lumen ratio in the myocardial vasculature of adult rats treated with L-NAME.

A decreased NO generation induces the synthesis of growth-promoting factors from the endothelium. The ACE activation would increase the formation of angiotensin II, which in turn directly induces vascular smooth muscle proliferation [44].

 Possibly, the factors involved in hyperplasia/hypertrophy of the smooth muscle cells of the microvasculature of newborns born to hypertensive mothers who received L-NAME during pregnancy are activation of the renin-angiotensin system and activation of the sympathetic nervous system that contributes to the remodeling of intramyocardial vessels [42].

In rats treated with L-NAME, the blood pressure increases via the reninangiotensin system, and, therefore, angiotensin II can promote the narrowing of the lumen of the microvasculature [45].

In neonates of hypertensive rats induced by L-NAME, in addition to cardiac microvasculature being affected, the pyloric musculature is also compromised, observing hypertrophy and hyperplasia of smooth muscle cells [46].

The rat offspring from L-NAME parents, with sustained NO-induced hypertension, had a remarkably higher blood pressure [47]. In addition to impairment in cardiovascular development, there are other damages in the offspring of rats treated with L-NAME as in the hippocampus, affecting cognitive and learning abilities [48].


**10. Congestion control**

Congestion in a packet switching network is a state in which the performance of the network degrades because of the saturation of network resources. Congestion could result in degradation of service quality to users. To avoid congestion, certain mechanisms have to be provided; such mechanisms are usually called congestion control.

#### **10.1 Categories of congestion control**

Congestion control policies can be categorized differently based on the objective of the policy, the time period of applying the policy, and the action taken to avoid congestion. In the following we will explain some of these policies.

Traffic Engineering 257

traffic. The selection of packets drop in this policy is completely uniform. Random Drop can

Congestion recovery tries to restore an operating state, when demand has exceeded capacity. Congestion avoidance is preventive in nature. It tries to keep the demand on the

**Congestion Indication:** The so-called Congestion Indication policy uses a similar technique as the Source Quench policy to inform the source gateway of congestion. The information is communicated in a single bit. The Congestion Experienced Bit (CEB) is set in the network header of the packets already being forwarded by a gateway. Based on the value of this bit, the end-system user should make an adjustment to the sending window. The Congestion Indication policy works based upon the total demand on the gateway. For fairness the total number of users causing the congestion is not considered. Only users who are sending more than their fair share (allowed bandwidth) should be asked to reduce their load, while others

**Fair Queuing:** Fair queuing is a congestion control policy where separate gateway output queues are maintained for individual end-systems on a source-destination-pair basis. When congestion occurs, packets are dropped from the longest queue. At the gateway, the processing and link resources are distributed to the end-systems on a round-robin basis. Round-robin is an arrangement of choosing all elements in a group equally in a circular.

A Bit-Round Fair Queuing algorithm was an improvement over the fair queuing. It computes the order of service to packets using their lengths, by using a technique that emulates a bit-by-bit round-robin discipline. In this case, long packets do not get an

Stochastic Fairness Queuing (SFQ) is a similar mechanism to Fair Queuing. SFQ looks up the source-destination address pair in the incoming packets and locates the appropriate queue that packet will have to be placed in. It uses a simple hash function to map from the sourcedestination address pair to a fixed set of queues. The price paid to implement SFQ is that it

Network control (NC) can be classified as centralized or distributed. In centralized network control, the route control and route computation commands are implemented and issued from one place. Each node in the network communicates with a central controller and it is the controller's responsibility to perform routing and signaling on behalf of all other nodes. In a distributed network control, each node maintains partial or full information about the network state and existing connections. Each node is responsible to perform routing and signaling. Therefore, coordination between nodes is required to alleviate the problem of contention.

Since its birth, the Internet (IP network) has employed a distributed NC paradigm. The Internet NC consists of many protocols. The functionality of resource discovery and management, topology discovery, and path computation and selection are the responsibility of routing protocols. Multiprotocol label switching (MPLS) has been proposed by IETF, to

Equal allocations of resources are provided to each source-destination pair.

advantage over short packets. Otherwise the round-robin would be unfair.

network at or near the point of maximum power, so that the congestion never occurs.

be categorized as Congestion recovery or congestion avoidance.

could attempt to increase their load where possible.

requires a potentially large number of queues.

**11. MPLS, and GMPLS traffic engineering**