**4.2 Renin-angiotensin system as a cause of preeclampsia**

The renin-angiotensin system (RAS) recognizes pregnancy very early. In the luteal phase of menstrual cycle, the RAS is activated under the influence of progesterone, and if pregnancy occurs, this RAS activation is maintained. This activation of RAS may be caused by progesterone that is natriuretic or it could be the "perceived under filling" of circulation by macula densa in early pregnancy. Juxtaglomerular apparatus synthesizes and releases renin, an aspartyl protease. Estrogen simultaneously binds to the promoter region of alpha-2 globulin angiotensinogen (AOGEN) and leads to the synthesis of angiotensinogen. Plasma

**Figure 6.** *Pathogenesis of preeclampsia in LACHD deficient fetus.*

#### **Figure 7.**

*Pathogenesis of preeclampsia in a nonresilient cardiovascular system. The autonomic nervous system, intrinsic smooth muscle reflexes, and the endothelium influence vascular tone.*

angiotensin II (AGII) rises and leads to the synthesis and release of aldosterone from the zona glomerulosa in the adrenal cortex. The pregnant women do not develop hypertension from the presser effects of AGII due to the downregulation of ATR1 receptors. The vessel responsive to adrenal cortisol is usually unaltered in pregnancy [20, 21].

Angiotensin II is very peculiar because its action depends on which of its two receptors it is acting. When AGII binds with AGI receptors, it causes vasoconstriction, but when it binds to AGII receptors, it causes vasodilation. If angiotensin I receptors are downregulated during pregnancy or by angiotensin receptor blockers like telmisartan or if angiotensin II receptors are upregulated during fetal life, it is a vasodilator.

Villous syncytiotrophoblast has high density of angiotensinase A (aminopeptidase A) which converts angiotensin II to angiotensin III [22, 23]. The increase in this angiotensinase activity is also responsible for downregulation of ATR1 receptors in normal pregnancy [24]. It was observed that during cesarean section in normal pregnancy, the uterine venous AGII is lower than the peripheral venous AGII. In preeclampsia pregnancy, uterine venous AGII are higher than peripheral AGII level [25].

In prospective studies it has been demonstrated that aminopeptidase A levels were high before the clinical syndrome of preeclampsia but levels were lower after preeclampsia clinically developed [24]. The initial rise in trophoblastic aminopeptidase could be an initial homeostatic response protecting placenta from the harmful effects of locally generated AGII.

The receptor for angiotensin IV is also called as insulin-regulated aminopeptidase (IRAP). High concentrations of IRAP are present on human placenta [26]. In the second half of pregnancy, the extracellular domain of this receptor is shed off. Angiotensin IV acts as an endogenous inhibitor of angiotensin-converting enzyme. It stimulates both RNA and DNA synthesis in endothelial cells and proliferation of endothelial cells. It can also increase the levels of plasminogen activator inhibitor

**15**

*Introductory Chapter: The Multiple Etiologies of Preeclampsia*

mRNA. It is a vasodilator at least in cerebral vessels. These features are important because angiotensin IV can be involved in local apoptosis and remodeling.

In preeclampsia there may be an impaired vasodilator response to endotheliumdependent agonists such as acetylcholine and bradykinin (**Figure 7**). Various adaptive mechanisms are employed at the fetomaternal interphase, and subsequently after 20 weeks, a clinically evident maternal syndrome of hypertension, edema, and proteinuria develops. The development of second stage of late vascular dysfunction can also happen independent of first stage. The uterine artery Doppler waveform becomes transformed into a high flow with low resistance at 22–24 weeks in normal gestation. However, in preeclampsia there is a latent preclinical stage with impaired intravascular volume expansion, hyperdynamic circulation, and a decreased cardiac output as clinical disease develops. This decreased cardiac output leads to renal and uteroplacental insufficiency. There may also be leaky capillaries leading to pulmonary and cerebral edema. Severe and early-onset preeclampsia has abnormal uterine artery waveform in preclinical stage and hypertension in clinical stage. Abnormal Doppler of uterine artery may be considered as a local noninvasive imaging of a more generalized systemic vasculopathy. This may mediate further cardiovascular risks. Women with preeclampsia are also two and a half times likely to die from ischemic heart disease in later life [27–29]. Several studies have been conducted showing preeclampsia association with the high pulsatility index of uterine artery. Raised uterine artery impedance is a marker of early endothelial dysfunction. It is associated with increased aortic pulse wave velocity and augmentation index in the first trimester of pregnancy that is the marker of future cardiovascular risk [30–32]. Increased homocysteine levels have also been implicated in both cardiovas-

Preeclampsia is a heterogeneous disease. The late-onset preeclampsia at or near term has low fetal and maternal morbidity. But the early-onset preeclampsia (1%) of all preeclampsia has significant risks. Prediction of risks and identification of subclinical disease are mandatory. The majority of at-risk groups in multigravida are chronic hypertension, pregestational and gestational diabetes, age, and multiple fetuses, whereas in primigravida only 14% have these risks. If there is preeclampsia in a multigravida, a nonplacental cause should be definitely considered. This suggests that there are multiple underlying etiologies of different clinical presentations. **Table 1** summarizes the likely etiopathogenesis in different clinical scenarios. Postpartum eclampsia can be predicted and monitored with central venous pressure and pulmonary capillary wedge pressure [34–36]. The maternal syndrome (proteinuria, edema, and hypertension) also has differences in time of onset, severity, and organ system involvement as highlighted in several studies [37–39]. There is a rising interest in galectin molecules for prediction of these subtypes (**Figure 8**). These clinical subpopulations need to be identified and preeclampsia predicted with rigorous definition of different biomarkers of different clinical phenotypes [40–44]. The future endeavors should be to identify subclinical disease in various clinical phenotypes with these potential biomarkers

**4.3 Noncompliant cardiovascular system as a cause of preeclampsia**

*DOI: http://dx.doi.org/10.5772/intechopen.86177*

cular risks and preeclampsia [33].

in prospective longitudinal studies.

**5. Conclusion**

mRNA. It is a vasodilator at least in cerebral vessels. These features are important because angiotensin IV can be involved in local apoptosis and remodeling.
