Preeclampsia: Novel Mechanisms and Potential Therapeutic Approaches

Abstract

Preeclampsia is a serious complication of pregnancy where it affects 5-8% of all pregnancies. It increases the morbidity and mortality of both the fetus and pregnant woman, especially in developing countries. It deleteriously affects several vital organs, including the kidneys, liver, brain, and lung. Although, the pathogenesis of preeclampsia has not yet been fully understood, growing evidence suggests that aberrations in the angiogenic factors levels and coagulopathy are responsible for the clinical manifestations of the disease. The common nominator of tissue damage of all these target organs is endothelial injury, which impedes their normal function. At the renal level, glomerular endothelial injury leads to the development of maternal proteinuria. Actually, peripheral vasoconstriction secondary to maternal systemic inflammation and endothelial cell activation is sufficient for the development of preeclampsia-induced hypertension. Similarly, preeclampsia can cause hepatic and neurologic dysfunction due to vascular damage and/or hypertension. Obviously, preeclampsia adversely affects various organs, however it is not yet clear whether pre-eclampsia per se adversely affects various organs or whether it exposes underlying genetic predispositions to cardiovascular disease that manifest in later life. The current review summarizes recent development in the pathogenesis of preeclampsia with special focus on novel diagnostic biomarkers and their relevance to potential therapeutic options for this disease state. Specifically, the review highlights the renal manifestations of the disease with emphasis on the involvement of angiogenic factors in vascular injury and on how restoration of the angiogenic balance affects renal and cardiovascular outcome of Preeclamptic women.

Keywords: endoglin; endothelium; fetus; kidney; maternity; placental growth factor (PlGF); preeclampsia; soluble growth factor receptor-sFlt.

FIGURE 1

(A) CVD death Kaplan–Meier survival according to gestational timing of preeclampsia. Survival analysis is based on 14, 403 pregnant women. A total of 481 had observed preeclampsia, and 266 died from cardiovascular disease (adopted with permission from Mongraw-Chaffin et al., 2010). (B) Cumulative risk of end-stage renal disease (ESRD) after first preeclampsia (adopted with permission from Vikse et al., 2008).

FIGURE 2

Aberrant placentation and angiogenesis in preeclampsia. In normal pregnancy, cytotrophoblasts of fetal origin invade the maternal spiral arteries and replace endothelial cell layer. This action converts the spiral arteries from narrow highly resistant vessels to high-caliber capacitance vessels, which are capable of providing sufficient blood and nutrition supply to the fetus. During the process of vascular invasion, the cytotrophoblasts differentiate from an epithelial to an endothelial phenotype, a process referred to as pseudovasculogenesis, or vascular mimicry (Right). In preeclampsia, cytotrophoblasts fails to acquire invasive endothelial phenotype features, thus the invasion of the spiral arteries is inadequate leaving them narrow and highly resistant (Left). Modified with permission from Lam et al. (2005) and Powe et al. (2011).

FIGURE 3

(A) Vascular function in normal pregnancy and (B) Vascular dysfunction in preeclampsia. In normal pregnancy there is angiogenic balance as evident by VEGF, PlGF, and TGF-β levels, which are necessary for normal blood vessel formation and endothelial function via eNOS activation and subsequent nitric oxide generation. The action of these factors is hampered in preeclampsia due to angiogenic imbalance, where soluble sFlt-1 and sEng act as scavengers for native VEGF, PlGF, and TGF-β, thus inducing endothelial dysfunction.

FIGURE 4

Preeclampsia-induced renal dysfunction. Under normal condition, VEGF plays a central role in maintaining the integrity of glomerular barrier as evident by healthy podocytes with normal foot process and slit diaphragm proteins. Under preeclamptic condition, angiogenic imbalance develops mainly due to sFlt-1 and sEng, leading to podocyte and endothelial damage in the glomerular filtration barrier and subsequently to the development of proteinuria.

FIGURE 5

Innovative approach for the elimination of the elevated levels of sFlt-1 by apheresis for the management of preeclampsia. The maternal blood flow through columns, which contains antibodies against sFlt1 in order to remove it from the circulation.