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

Authors
  • Stanhewicz, Anna E1
  • Jandu, Sandeep2
  • Santhanam, Lakshmi2
  • Alexander, Lacy M3
  • 1 Department of Kinesiology, The Pennsylvania State University, University Park, PA 16802, U.S.A. [email protected]
  • 2 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A.
  • 3 Department of Kinesiology, The Pennsylvania State University, University Park, PA 16802, U.S.A.
Type
Published Article
Journal
Clinical Science
Publisher
Portland Press
Publication Date
Dec 22, 2017
Volume
131
Issue
23
Pages
2777–2789
Identifiers
DOI: 10.1042/CS20171292
PMID: 29042489
Source
Medline
Keywords
License
Unknown

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.

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