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

Anna E. Stanhewicz, Sandeep Jandu, Lakshmi Santhanam, Lacy M. Alexander

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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 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 ETBR signaling. Furthermore, altered ETBR function contributes to diminished endothelium-dependent dilation in previously preeclamptic women.

Original languageEnglish (US)
Pages (from-to)2777-2789
Number of pages13
JournalClinical Science
Volume131
Issue number23
DOIs
StatePublished - Dec 1 2017

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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