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

Department of Pharmacology and Toxicology ,Faculty of Medicine ,American University of Beirut ,Beirut ,Lebanon
Fardoun, Manal;
Department of Biomedical and Dental Sciences and Morphofunctional Imaging ,University of Messina ,Messina ,Italy
Mondello, Stefania;
Department of Emergency Medicine ,University of Florida ,Gainesville ,FL ,United States
Kobeissy, Firas;
Department of Basic Medical Sciences ,College of Medicine ,QU Health ,Qatar University ,Doha ,Qatar
Eid, Ali H.

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 17β-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 (α 2C -AR), the sole mediator of cold-induced constriction of cutaneous arterioles. This induced expression occurs through the cyclic adenosine monophosphate → exchange protein activated by cAMP→ Ras-related protein 1→ c-Jun N-terminal kinase→ 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 α 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 Our current working hypothesis and unpublished observations further cement this finding, as G1, a GPER agonist, mimics while G15, a GPER antagonist, abrogates estrogen’s effect on the expression of vascular α 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.


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