Abstract 446: Selective Activation of G-Protein-Coupled Estrogen Receptor GPR30 Inhibits Vasoconstriction and Induces Vascular Smooth Muscle Cell ERK1/2 Phosphorylation
Endogenous estrogens are cardioprotective and exert rapid dilator effects in premenopausal women. The natural estrogen, 17β-estradiol (E2), is a non-selective agonist of all three known estrogen receptors (ERα, ERβ, and GPR30), however the individual contribution of the individual receptors for E2-mediated cellular responses in the vascular wall is unknown. We have recently found high expression levels of GPR30 in vascular smooth muscle cells and in intact arteries ( Hypertension. 2007; 49:1358–63). However, whether activation of this receptor has effects on vascular reactivity is unknown. The present study investigated whether GPR30 affects vascular tone in C57BL6/J mouse aorta and carotid artery. Rings were incubated for 30 min either with the selective GPR30 agonist G1 (Merck), the non-selective estrogen receptor agonist E2 (both at 1 μM), or vehicle control (ethanol, 0.1%), and vascular reactivity to the α adrenergic agonist phenylephrine (PE; 10 μM) or serotonin (5-hydroxytryptamine, 5-HT; 1 μM) was recorded. Contractile responses were normalized to KCl (100 mM). In the carotid artery but not in the aorta, preincubation with G1 suppressed PE-induced contraction by −30±7% (p<0.05 vs. control) whereas PE-mediated contraction was unaffected by E2 (n.s.). Vascular contractility in response to 5-HT was markedly reduced by G1 (−52±9%) and also by E2 (−51±14%, both p<0.05 <0.05 vs. control) in the carotid artery, however neither treatment had any effects in the aorta. In cultured human vascular smooth muscle cells, stimulation with G1 (10nM or 100nM) induced phosphorylation of Erk-1/2. These data indicate for the first time that activation of the novel membrane-bound G-protein-coupled estrogen receptor GPR30 by the selective agonist G1 has indirect vasodilator effects by inhibiting vasoconstriction in selected arterial vascular beds. GPR30 activation also causes phophorylation of Erk-1/2 in human vascular smooth muscle. Activation of GPR30 is likely to contribute to the direct and indirect vasodilator effects of natural estrogen such as E2 and could be a novel therapeutic option for the treatment of vascular diseases such as atherosclerosis.