Molecular determinants of microvascular dysfunction in hypertensive pregnancy and preeclampsia

Abstract

Preeclampsia is a pregnancy-related disorder characterized by hypertension and often fetal intrauterine growth restriction, but the underlying mechanisms are unclear. Defective placentation and apoptosis of invasive cytotrophoblasts cause inadequate remodeling of spiral arteries, placental ischemia, and reduced uterine perfusion pressure (RUPP). RUPP causes imbalance between the anti-angiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin and the pro-angiogenic vascular endothelial growth factor and placental growth factor, and stimulates the release of proinflammatory cytokines, hypoxia-inducible factor, reactive oxygen species, and angiotensin AT₁ receptor agonistic autoantibodies. These circulating factors target the vascular endothelium, smooth muscle and various components of the extracellular matrix. Generalized endotheliosis in systemic, renal, cerebral, and hepatic vessels causes decreases in endothelium-derived vasodilators such as nitric oxide, prostacyclin and hyperpolarization factor, and increases in vasoconstrictors such as endothelin-1 and thromboxane A2. Enhanced mechanisms of vascular smooth muscle contraction, such as intracellular Ca²⁺ , protein kinase C, and Rho-kinase cause further increases in vasoconstriction. Changes in matrix metalloproteinases and extracellular matrix cause inadequate vascular remodeling and increased arterial stiffening, leading to further increases in vascular resistance and hypertension. Therapeutic options are currently limited, but understanding the molecular determinants of microvascular dysfunction could help in the design of new approaches for the prediction and management of preeclampsia.

Keywords: endothelium; extracellular matrix; microvessels; placental ischemia; vascular smooth muscle.

Fig. 1.

Mechanisms of microvascular dysfunction in HTN-Preg. Initial reduction of uteroplacental perfusion pressure (RUPP) and uteroplacental ischemia causes the release of bioactive and circulating factors, which target blood vessels leading to decreased endothelium-dependent vascular relaxation pathways, increased endothelin-1 (ET-1) and mechanisms of VSM contraction, and abnormalities in MMPs expression/activity and increased collagen deposition in extracellular matrix (ECM), resulting in increased vascular resistance and HTN-Preg. AT₁-AA, AngII AT₁R agonistic autoantibodies; EDHF, endothelium-derived hyperpolarizing factor; HIF, hypoxia-inducible factor; HO, hemeoxygenase, IL-6, interleukin-6; NO, nitric oxide; PKC, protein kinase C; PlGF, placental growth factor; ROS, reactive oxygen species; sEng, soluble endoglin; sFlt-1, soluble fms-like tyrosine kinase-1; TNFα, tumor necrosis factor-α; VEGF, vascular endothelial growth factor; VSM, vascular smooth muscle