GPER regulates endothelin-dependent vascular tone and intracellular calcium

Abstract

AimsAn increase in intracellular vascular smooth muscle cell calcium concentration (VSMC [Ca2+]i) is essential for endothelin-1 (ET-1)-induced vasoconstriction. Based on previous findings that activation of the G protein-coupled estrogen receptor (GPER) inhibits vasoconstriction in response to ET-1 and regulates [Ca2+]i in cultured VSMC, we investigated whether endogenous GPER regulates ET-1-induced changes in VSMC [Ca2+]i and constriction of intact arteries. Main methodsPressurized carotid arteries of GPER-deficient (GPER0) and wildtype (WT) mice were loaded with the calcium indicator fura 2-AM. Arteries were stimulated with the GPER-selective agonist G-1 or solvent followed by exposure to ET-1. Changes in arterial diameter and VSMC [Ca2+]i were recorded simultaneously. Vascular gene expression levels of ETA and ETB receptors were determined by qPCR. Key findingsET-1-dependent vasoconstriction was increased in arteries from GPER0 compared to arteries from WT mice. Despite the more potent vasoconstriction to ET-1, GPER deficiency was associated with a marked reduction in the ET-1-stimulated VSMC [Ca2+]i increase, suggesting an increase in myofilament force sensitivity to [Ca2+]i. Activation of GPER by G-1 had no effect on vasoconstriction or VSMC [Ca2+]i responses to ET-1, and expression levels of ETA or ETB receptor were unaffected by GPER deficiency. SignificanceThese results demonstrate that endogenous GPER inhibits ET-1-induced vasoconstriction, an effect that may be associated with reduced VSMC Ca2+ sensitivity. This represents a potential mechanism through which GPER could contribute to protective effects of endogenous estrogen in the cardiovascular system.