Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia

Abstract

Maternal vascular adaptation to pregnancy is critically important to expand the capacity for blood flow through the uteroplacental unit to meet the needs of the developing fetus. Failure of the maternal vasculature to properly adapt can result in hypertensive disorders of pregnancy such as preeclampsia (PE). Herein, we review the endocrinology of maternal adaptation to pregnancy and contrast this with that of PE. Our focus is specifically on those hormones that directly influence endothelial cell function and dysfunction, as endothelial cell dysfunction is a hallmark of PE. A variety of growth factors and cytokines are present in normal vascular adaptation to pregnancy. However, they have also been shown to be circulating at abnormal levels in PE pregnancies. Many of these factors promote endothelial dysfunction when present at abnormal levels by acutely inhibiting key Ca²⁺ signaling events and chronically promoting the breakdown of endothelial cell-cell contacts. Increasingly, our understanding of how the contributions of the placenta, immune cells, and the endothelium itself promote the endocrine milieu of PE is becoming clearer. We then describe in detail how the complex endocrine environment of PE affects endothelial cell function, why this has contributed to the difficulty in fully understanding and treating this disorder, and how a focus on signaling convergence points of many hormones may be a more successful treatment strategy.

Keywords: Ca2+; cytokines; endocrinology; preeclampsia; pregnancy adaptation.

Figure 1. Proposed Mechanism of Endothelial Dysfunction in Preeclampsia

A diverse array of inflammatory hormones are altered in the circulation of late-term PE pregnancies compared to normal pregnancies. Together, these result in activation of kinase signaling pathways such as Src, ERK, PKC, and possibly others. Activation of these pathways results in both acute and long-term changes at the level of the plasma membrane. Acutely, closure of Cx43 alone results in immediate endothelial dysfunction by reducing the capacity of endothelial cells to coordinate Ca2+ responses needed to stimulate production of vasodilators (NO, PGI2). Longer term, further damage to cell junctional proteins such as ZO-1 and VECadherin (by altered turnover or degradation by MMPs) causes a reduction in cell endothelial monolayer integrity and even vessel leakage (edema).