GPER regulates endothelin-dependent vascular tone and intracellular calcium.

AIMS

An increase in intracellular vascular smooth muscle cell calcium concentration (VSMC Ca(2+)) 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 Ca(2+) in cultured VSMC, we investigated whether endogenous GPER regulates ET-1-induced changes in VSMC Ca(2+) and constriction of intact arteries.

MAIN METHODS

Pressurized carotid arteries of GPER-deficient (GPER(0)) 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 Ca(2+) were recorded simultaneously. Vascular gene expression levels of ET(A) and ET(B) receptors were determined by qPCR.

KEY FINDINGS

ET-1-dependent vasoconstriction was increased in arteries from GPER(0) 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 Ca(2+) increase, suggesting an increase in myofilament force sensitivity to Ca(2+). Activation of GPER by G-1 had no effect on vasoconstriction or VSMC Ca(2+) responses to ET-1, and expression levels of ET(A) or ET(B) receptor were unaffected by GPER deficiency.

SIGNIFICANCE

These results demonstrate that endogenous GPER inhibits ET-1-induced vasoconstriction, an effect that may be associated with reduced VSMC Ca(2+) sensitivity. This represents a potential mechanism through which GPER could contribute to protective effects of endogenous estrogen in the cardiovascular system.