Risk Factors and Mediators of the Vascular Dysfunction Associated with Hypertension in Pregnancy

Abstract

Normal pregnancy is associated with significant hemodynamic changes and vasodilation in the uterine and systemic circulation in order to meet the metabolic demands of the mother and developing fetus. Hypertension in pregnancy (HTN-Preg) and preeclampsia (PE) are major complications and life-threatening conditions to both the mother and fetus. PE is precipitated by various genetic, dietary and environmental factors. Although the initiating events of PE are unclear, inadequate invasion of cytotrophoblasts into the uterine artery is thought to reduce uteroplacental perfusion pressure and lead to placental ischemia/hypoxia. Placental hypoxia induces the release of biologically active factors such as growth factor inhibitors, anti-angiogenic proteins, inflammatory cytokines, reactive oxygen species, hypoxia-inducible factors, and antibodies to vascular angiotensin II receptor. These bioactive factors affect the production/activity of various vascular mediators in the endothelium, smooth muscle and extracellular matrix, leading to severe vasoconstriction and HTN. As an endothelial cell disorder, PE is associated with decreased vasodilator mediators such as nitric oxide, prostacyclin and hyperpolarizing factor and increased vasoconstrictor mediators such as endothelin, angiotensin II and thromboxane A2. PE also involves enhanced mechanisms of vascular smooth muscle contraction including intracellular free Ca2+ concentration ([Ca2+]i), and [Ca2+]i sensitization pathways such as protein kinase C, Rho-kinase and mitogen-activated protein kinase. Changes in extracellular matrix composition and matrix metalloproteases activity also promote vascular remodeling and further vasoconstriction in the uterine and systemic circulation. Characterization of the predisposing risk factors, the biologically active factors, and the vascular mediators associated with PE holds the promise for early detection, and should help design specific genetic and pharmacological tools for the management of the vascular dysfunction associated with HTN-Preg.

The Pathophysiology of Endothelial Function in Pregnancy and the Usefulness of Endothelial Markers

“…Increased MMP production can be induced by oxidized lipids, reactive oxygen species, CD-40 ligation, inflammatory cytokines, tenascin-C derived from macrophages, and hemodynamic stress [34][35][36][37][38] . The situation during pregnancy is different 39 . Changes in extracellular matrix composition and matrix metalloproteinase activity also promote vascular remodeling but only in the uterus.…”

Genetic, immune and vasoactive factors in the vascular dysfunction associated with hypertension in pregnancy

“…PE may also be associated with fetal intrauterine growth restriction (IUGR) and reduced birth weight. If untreated, PE can lead to eclampsia with severe neurovascular complications including severe HTN and convulsions [2]. …”

GSTA1 gene variation associated with gestational hypertension and its involvement in pregnancy-related pathogenic conditions

“…In Italy, the prevalence of pregnancies complicated by hypertension is about 3%, 1% of which involve preeclampsia [4]. The pathogenesis of GH is related to a number of biological mechanisms that include alteration of the vascular system, poor placentation, placental hypoxia/ischemia, and increased release of many different biologically active factors, eventually causing generalized vascular dysfunction [5]. In particular, these multiple pathogenetic mechanisms are strongly linked to a numerous genetic and environmental factors that contribute to GH susceptibility [6].…”