Estrogen increases expression of vascular alpha 2C adrenoceptor through the cAMP/Epac/JNK/AP-1 pathway and potentiates cold-induced vasoconstriction
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24 janvier 2025
- 10938/25166
- 32407896.0
- 2-s2.0-85086744901
Ce document est lié à :
Vascular Pharmacology
Mots-clés
Ap-1 Estrogen Jnk Raynaud's phenomenon Vasoconstriction Α2c-adrenergic receptor Animals Arterioles Cells, cultured Cold temperature Cyclic amp Estradiol Guanine nucleotide exchange factors Humans Jnk mitogen-activated protein kinases Male Mice, inbred c57bl Muscle, smooth, vascular Myocytes, smooth muscle Raynaud disease Receptors, adrenergic, alpha-2 Signal transduction Tail Transcription factor ap-1 Up-regulation Ab 120657 Alpha 2c adrenergic receptor Anthra[1,9 cd]pyrazol 6(2h) one Binding protein Epac protein Esi 09 Protein inhibitor Stress activated protein kinase Transcription factor ap 1 Unclassified drug Adra2c protein, human Alpha 2 adrenergic receptor Guanine nucleotide exchange factor Rapgef3 protein, human Animal cell Animal experiment Animal tissue Arteriole Article Binding site Cold Controlled study Drug antagonism Drug mechanism Enzyme activation Ex vivo study Genetic transfection Human Human cell In vitro study Mouse Nonhuman Priority journal Promoter region Protein expression Protein function Protein transport Raynaud phenomenon Transient transfection Upregulation Vascular smooth muscle cell Animal C57bl mouse Cell culture Drug effect Enzymology Genetics Metabolism Pathophysiology Smooth muscle cell Vascular smooth muscle VascularizationSujets proches
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Fardoun et al., « Estrogen increases expression of vascular alpha 2C adrenoceptor through the cAMP/Epac/JNK/AP-1 pathway and potentiates cold-induced vasoconstriction », American University of Beirut ScholarWorks
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Résumé
Cutaneous cold-induced vasoconstriction is a normal physiological reaction mediated by alpha 2C-adrenergic receptors (α2C-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-β estradiol (estrogen) upregulates α2C-ARs in human VSMCs via a cAMP/Epac/Rap pathway. We also showed that cAMP acts through JNK to increase α2C-AR expression. However, whether estrogen employs JNK to regulate α2C-AR is not investigated. Knowing that the α2C-AR promoter harbors an activator protein-1 (AP-1) binding site that can be potentially activated by JNK, we hypothesized that estrogen regulates α2C-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 μM; an Epac inhibitor), abolished estrogen-induced JNK activation. In addition, pre-treatment with SP600125 (3 μM; a JNK specific inhibitor) abolished estrogen-induced expression of α2C-AR. Importantly, estrogen-induced activation of α2C-AR promoter was attenuated with SP600125. Moreover, transient transfection of VSMCs with an Epac dominant negative mutant (Epac-DN) abolished estrogen-induced activation of α2C-AR promoter. However, co-transfection of constitutively active JNK mutant overrode the inhibitory effect of Epac-DN on α2C-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 α2C-AR promoter abolished its activation by estrogen. This in vitro estrogen-increased α2C-AR expression was mirrored by an increase in the ex vivo functional responsiveness of arterioles. Indeed, estrogen potentiated α2C-AR-mediated cold-induced vasoconstriction, which was abolished by SP600125. Collectively, these results indicate that estrogen upregulates α2C-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. © 2020
