Alterations in endothelin type B receptor contribute to microvascular dysfunction in women who have had preeclampsia.

Microvascular dysfunction originating during a preeclamptic pregnancy persists postpartum and probably contributes to increased CVD risk in these women. One putative mechanism contributing to this dysfunction is increased vasoconstrictor sensitivity to endothelin-1 (ET-1), mediated by alterations in ET-1 receptor type-B (ET _B R). We evaluated ET-1 sensitivity, ET _A R, and ET _B R contributions to ET-1-mediated constriction, and the mechanistic role of ET _B R in endothelium-dependent dilation in vivo in the microvasculature of postpartum women who had preeclampsia (PrEC, n =12) and control women who had a healthy pregnancy (HC, n =12). We hypothesized that (1) PrEC would have a greater vasoconstrictor response to ET-1, and (2) reduced ET _B R-mediated dilation. We further hypothesized that ET _B R-blockade would attenuate endothelium-dependent vasodilation in HC, but not PrEC. Microvascular reactivity was assessed by measurement of cutaneous vascular conductance responses to graded infusion of ET-1 (10 ^-20 -10 ^-8 mol/l), ET-1 + 500 nmol/l BQ-123 (ET _A R-blockade), and ET-1 + 300 nmol/l BQ-788 (ET _B R-blockade), and during graded infusion of acetylcholine (ACh, 10 ^-7 -10 ² mmol/l) and a standardized local heating protocol with and without ET _B R-inhibition. PrEC had an increased vasoconstriction response to ET-1 ( P =0.02). PrEC demonstrated reduced dilation responses to selective ET _B R stimulation with ET-1 ( P =0.01). ET _B R-inhibition augmented ET-1-mediated constriction in HC ( P =0.01) but attenuated ET-1-mediated constriction in PrEC ( P =0.003). ET _B R-inhibition attenuated endothelium-dependent vasodilation responses to 100mmol/l ACh ( P =0.04) and local heat ( P =0.003) in HC but increased vasodilation (ACh: P =0.01; local heat: P =0.03) in PrEC. Women who have had preeclampsia demonstrate augmented vasoconstrictor sensitivity to ET-1, mediated by altered ET _B R signaling. Furthermore, altered ET _B R function contributes to diminished endothelium-dependent dilation in previously preeclamptic women.
(© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)