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Raynaud's phenomenon, which results from exaggerated cold-induced vasoconstriction, is more prevalent in females than males. We previously showed that estrogen increases the expression of alpha 2C-adrenoceptors (α2C-AR), the sole mediator of cold-induced vasoconstriction. This effect of estrogen is reproduced by the cell-impermeable form of the hormone (E2:bovine serum albumin [BSA]), suggesting a role of the membrane estrogen receptor, G-protein-coupled estrogen receptor [GPER], in E2-induced α2C-AR expression. We also previously reported that E2upregulates α2C-AR in microvascular smooth muscle cells (VSMCs) via the cAMP/Epac/Rap/JNK/AP-1 pathway, and that E2:BSA elevates cAMP levels. We, therefore, hypothesized that E2uses GPER to upregulate α2C-AR through the cAMP/Epac/JNK/AP-1 pathway. Our results show that G15, a selective GPER antagonist, attenuates the E2-induced increase in α2C-AR transcription. G-1, a selective GPER agonist, induced α2C-AR transcription, which was concomitant with elevated cAMP levels and JNK activation. Pretreatment with ESI09, an Epac inhibitor, abolished G-1-induced α2C-AR upregulation and JNK activation. Moreover, pretreatment with SP600125, a JNK-specific inhibitor, but not H89, a PKA-specific inhibitor, abolished G-1-induced α2C-AR upregulation. In addition, transient transfection of an Epac dominant negative mutant (Epac-DN) attenuated G-1-induced activation of the α2C-AR promoter. This inhibitory effect of Epac-DN on the α2C-AR promoter was overridden by the cotransfection of constitutively active JNK mutant. Furthermore, mutation of AP-1 site in the α2C-AR promoter abrogated G1-induced expression. Collectively, these results indicate that GPER upregulates α2C-AR through the cAMP/EPAC/JNK/AP-1 pathway. These findings unravel GPER as a new mediator of cold-induced vasoconstriction, and present it as a potential target for treating Raynaud's phenomenon in estrogen-replete females.

Raynaud's Phenomenon (RP) results from exaggerated cold-induced vasoconstriction. RP patients suffer from vasospastic attacks and compromised digital blood perfusion leading to a triple color change at the level the fingers. Severe RP may cause ulcers and threaten tissue viability. Many drugs have been used to alleviate the symptoms of RP. These include calcium-channel blockers, cGMP-specific phosphodiesterase type 5 inhibitors, prostacyclin analogs, and angiotensin receptor blockers. Despite their variety, these drugs do not treat RP but rather alleviate its symptoms. To date, no drug for RP has been yet approved by the U.S Food and Drugs Administration. Cilostazol is a selective inhibitor of phosphodiesterase-III, originally prescribed to treat intermittent claudication. Owing to its antiplatelet and vasodilating properties, cilostazol is being repurposed as a potential drug for RP. This review focuses on the different lines of action of cilostazol serving to enhance blood perfusion in RP patients.