KL 30 Vascular mediators leading to hypertension in pregnancy

Abstract

Preeclampsia is characterized by generalized endothelial dysfunction. This endothelial dysfunction underlies the hypertension and proteinuria as well as other complications in preeclampsia and is associated with an increased production of the extremely potent, endothelium-dependent vasoconstrictor endothelin-1 (ET-1) and a decrease in the production of the endothelium-dependent vasodilators nitric oxide and prostacyclin. Angiogenic imbalance, due to increased placental production of soluble fms-tyrosine kinase −1 (sFlt-1) leading to decreases in free plasma concentrations of the proangiogenic placenta growth factor and vascular endothelial growth factor (VEGF), is considered to be the main mediator of the endothelial dysfunction in preeclampsia. Recent studies in pregnant women with and without preeclampsia have shown that the degree of activation of the endothelin system is directly related to the increased levels of soluble fms-tyrosine kinase-1 (sFlt-1). In turn this activation of the endothelin has shown to underlie the suppression of plasma renin and aldosterone in preeclamptic compared to normal gestations. That the angiogenic imbalance is a mediator of the increase ET-1 levels in preeclampsia is supported by experimental studies and by studies in patients with cancer treated with VEGF-inhibitors aimed to impair angiogenesis and tumor growth. In these patients anti-angiogenic treatment is associated with increased ET-1 levels. In addition, in animals exposed to VEGF-inhibition the rise in blood pressure and proteinuria can almost completely be prevented by endothelin receptor blockade, proving that an activated endothelin system is instrumental for the rise in blood pressure and proteinuria. These observations may imply that preeclampsia is treatable with agents that interfere with placental sFlt-1 production, resulting in lower plasma ET-1 levels, as has recently been reported for proton pump inhibitors or alternatively with endothelin receptor blockers, providing that the latter agents are safe in the second and third trimester of pregnancy when organogenesis had been completed.