G protein estrogen receptor as a potential therapeutic target in Raynaud's phenomenon

Exaggerated cold-induced vasoconstriction can precipitate a pathogenesis called Raynaud's phenomenon (RP). Interestingly, RP is significantly more prevalent in females than age-matched men, highlighting the potential implication of 17 beta-estradiol (E-2) in the etio-pathogenesis of this disease. Indeed, we have previously reported that E-2 stimulates the expression of vascular alpha 2C-adrenoceptors (alpha(2C)-AR), the sole mediator of coldinduced constriction of cutaneous arterioles. This induced expression occurs through the cyclic adenosine monophosphate -> exchange protein activated by cAMP & RARR; Ras-related protein 1 -> c-Jun N-terminal kinase & RARR; activator protein-1 (cAMP/Epac/Rap/JNK/AP-1 pathway). On the basis that estrogen-induced rapid cAMP accumulation and JNK activation occurs so rapidly we hypothesized that a non-classic, plasma membrane estrogen receptor was the mediator. We then showed that an impermeable form of E-2, namely E-2:BSA, mimics E-2 effects suggesting a role for the membranous G-protein coupled estrogen receptor (GPER) in E-2-induced alpha(2C)-AR expression. Our current working hypothesis and unpublished observations further cement this finding, as G1, a GPER agonist, mimics while G15, a GPER antagonist, abrogates estrogen's effect on the expression of vascular alpha(2C)-AR. These, and other observations, highlight the potential of GPER as a tractable target in the management of RP, particularly in pre-menopausal women.