Role of GPER in estrogen-dependent nitric oxide formation and vasodilation

The Journal of Steroid Biochemistry and Molecular Biology
Natalie C FredetteEric R Prossnitz

Abstract

Estrogens are potent regulators of vasomotor tone, yet underlying receptor- and ligand-specific signaling pathways remain poorly characterized. The primary physiological estrogen 17β-estradiol (E2), a non-selective agonist of classical nuclear estrogen receptors (ERα and ERβ) as well as the G protein-coupled estrogen receptor (GPER), stimulates formation of the vasodilator nitric oxide (NO) in endothelial cells. Here, we studied the contribution of GPER signaling in E2-dependent activation of endothelial NO formation and subsequent vasodilation. Employing E2 and the GPER-selective agonist G-1, we investigated eNOS phosphorylation and NO formation in human endothelial cells, and endothelium-dependent vasodilation in the aortae of wild-type and Gper-deficient mice. Both E2 and G-1 induced phosphorylation of eNOS at the activation site Ser1177 to similar extents. Endothelial NO production to E2 was comparable to that of G-1, and was substantially reduced after pharmacological inhibition of GPER. Similarly, the clinically used ER-targeting drugs 4OH-tamoxifen, raloxifene, and ICI182,780 (faslodex, fulvestrant™) induced NO formation in part via GPER. We identified c-Src, EGFR, PI3K and ERK signaling pathways to be involved in GPER-d...Continue Reading

Citations

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Aug 14, 2020·American Journal of Physiology. Cell Physiology·Natalie C FredetteNaohiro Terada
Nov 1, 2020·The Journal of Pharmacology and Experimental Therapeutics·Eman Y Gohar, David M Pollock
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Mar 13, 2017·The Journal of Steroid Biochemistry and Molecular Biology·Eric R Prossnitz
May 6, 2021·British Journal of Pharmacology·Quynh Nhu DinhChristopher G Sobey
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