4.5 Article

Estrogen increases expression of vascular alpha 2C adrenoceptor through the cAMP/Epac/JNK/AP-1 pathway and potentiates cold-induced vasoconstriction

Journal

VASCULAR PHARMACOLOGY
Volume 131, Issue -, Pages -

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.vph.2020.106690

Keywords

Raynaud's phenomenon; alpha(2C)-adrenergic receptor; Estrogen; JNK; AP-1; Vasoconstriction

Funding

  1. American University of Beirut-Faculty of Medicine [320133]
  2. National Center for Scientific Research award

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Cutaneous cold-induced vasoconstriction is a normal physiological reaction mediated by alpha 2C-adrenergic receptors (alpha(2C)-ARs) expressed in vascular smooth muscle cells (VSMCs). When this reaction is exaggerated, Raynaud's phenomenon (RP) ensues. RP is more prevalent in females compared to age-matched men. We previously established that 17-beta estradiol (estrogen) upregulates alpha(2C)-ARs in human VSMCs via a cAMP/Epac/Rap pathway. We also showed that cAMP acts through JNK to increase alpha(2C)-AR expression. However, whether estrogen employs JNK to regulate alpha(2C)-AR is not investigated. Knowing that the alpha(2C)-AR promoter harbors an activator protein-1 (AP-1) binding site that can be potentially activated by JNK, we hypothesized that estrogen regulates a2C-AR expression through an Epac/JNK/AP-1 pathway. Our results show that estrogen (10-10 M) activated JNK in human VSMCs extracted from cutaneous arterioles. Pretreatment with ESI09 (10 mu M; an Epac inhibitor), abolished estrogen-induced JNK activation. In addition, pre-treatment with SP600125 (3 mu M; a JNK specific inhibitor) abolished estrogen-induced expression of alpha(2C)-AR. Importantly, estrogen-induced activation of alpha(2C)-AR promoter was attenuated with SP600125. Moreover, transient transfection of VSMCs with an Epac dominant negative mutant (Epac-DN) abolished estrogen-induced activation of alpha(2C)-AR promoter. However, cotransfection of constitutively active JNK mutant overrode the inhibitory effect of Epac-DN on alpha(2C)-AR promoter. Moreover, estrogen caused a concentration-dependent increase in the activity of AP-1-driven reporter construct. Mutation of AP-1 site in the alpha(2C)-AR promoter abolished its activation by estrogen. This in vitro estrogen-increased alpha(2C)-AR expression was mirrored by an increase in the ex vivo functional responsiveness of arterioles. Indeed, estrogen potentiated alpha(2C)-AR-mediated cold-induced vasoconstriction, which was abolished by SP600125. Collectively, these results indicate that estrogen upregulates alpha(2C)-AR expression via an EPAC-mediated JNK/AP-1-dependent mechanism. These results provide an insight into the mechanism by which exaggerated cold-induced vasoconstriction occurs in estrogen-replete females and identify Epac and JNK as potential targets for the treatment of RP.

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