Molecular and vascular targets in the pathogenesis and management of the hypertension associated with preeclampsia

Abstract

Normal pregnancy is associated with significant hemodynamic changes and vasodilation of the uterine and systemic circulation in order to meet the metabolic demands of the mother and developing fetus. Preeclampsia (PE) is one of the foremost complications of pregnancy and a major cause of maternal and fetal mortality. The pathophysiological mechanisms of PE have been elusive, but some parts of the puzzle have begun to unravel. Genetic factors such as leptin gene polymorphism, environmental and dietary factors such as Ca(2+) and vitamin D deficiency, and co-morbidities such as obesity and diabetes may increase the susceptibility of pregnant women to develop PE. An altered maternal immune response may also play a role in the development of PE. Although the pathophysiology of PE is unclear, most studies have implicated inadequate invasion of cytotrophoblasts into the uterine artery, leading to reduced uteroplacental perfusion pressure (RUPP) and placental ischemia/hypoxia. Placental ischemia induces the release of biologically active factors such as growth factor inhibitors, anti-angiogenic factors, inflammatory cytokines, reactive oxygen species, hypoxia-inducible factors, and antibodies to vascular angiotensin II (AngII) receptor. These bioactive factors could cause vascular endotheliosis and consequent increase in vascular resistance and blood pressure, as well as glomerular endotheliosis with consequent proteinuria. The PE-associated vascular endotheliosis could be manifested as decreased vasodilator mediators such as nitric oxide, prostacyclin and hyperpolarizing factor and increased vasoconstrictor mediators such as endothelin-1, AngII and thromboxane A₂. PE could also involve enhanced mechanisms of vascular smooth muscle contraction including intracellular Ca(2+), and Ca(2+) sensitization pathways such as protein kinase C and Rho-kinase. PE-associated changes in the extracellular matrix composition and matrix metalloproteinases activity also promote vascular remodeling and further vasoconstriction in the uterine and systemic circulation. Some of these biologically active factors and vascular mediators have been proposed as biomarkers for early prediction or diagnosis of PE, and as potential targets for prevention or treatment of the disease.

Fig. 1

Risk factors and pathogenesis of preeclampsia (PE). Genetic, environmental and immune factors cause shallow placentation and RUPP during late pregnancy and trigger the release of circulating factors, which affect the systemic blood vessels and lead to generalized vasoconstriction, increased vascular resistance and HTN-Preg. The bioactive factors could injure the kidney leading to increased plasma volume and severe HTN, as well as glomerular endotheliosis and proteinuria. Increased cerebral vascular permeability and edema lead to seizures and life-threatening eclampsia.

Fig. 2

Circulating bioactive factors and vascular mediators during PE. Placental hypoxia/ischemia triggers the release of circulating factors in the plasma and cause a decrease in the release of vasodilators from the endothelium, an increase in vasoconstriction in VSM and the expression of MMPs and vascular remodeling in the adventitia. sEng is a TGF-β antagonist that blocks the TβRII receptor, and sFlt-1 is a VEGF antagonist that blocks the Flt-1 receptor. Solid arrows indicate stimulation. Interrupted arrows indicate inhibition.