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

作者：Stanhewicz Anna E^*; Jandu Sandeep; Santhanam Lakshmi; Alexander Lacy M

来源：Clinical Science, 2017, 131(23): 2777-2789.

DOI：10.1042/CS20171292

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 (ETBR). We evaluated ET-1 sensitivity, ETAR, and ETBR contributions to ET-1-mediated constriction, and the mechanistic role of ETBR 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 ETBR-mediated dilation. We further hypothesized that ETBR-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 (ETAR-blockade), and ET-1 + 300 nmol/l BQ-788 (ETBR-blockade), and during graded infusion of acetylcholine (ACh, 10-7-102 mmol/l) and a standardized local heating protocol with and without ETBR-inhibition. PrEC had an increased vasoconstriction response to ET-1 (P = 0.02). PrEC demonstrated reduced dilation responses to selective ETBR stimulation with ET-1 (P = 0.01). ETBR-inhibition augmented ET-1-mediated constriction in HC (P = 0.01) but attenuated ET-1-mediated constriction in PrEC (P = 0.003). ETBR-inhibition attenuated endothelium-dependent vasodilation responses to 100 mmol/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 ETBR signaling. Furthermore, altered ETBR function contributes to diminished endothelium-dependent dilation in previously preeclamptic women.

• 出版日期2017-12-1