Vasodilation by GPER in mesenteric arteries involves both endothelial nitric oxide and smooth muscle cAMP signaling.
Our previous work showed that chronic activation of the membrane-bound estrogen receptor GPR30/GPER significantly lowers blood pressure in ovariectomized hypertensive mRen2.Lewis female rats which may, in part, reflect direct vasodilatory actions. The current study assessed the hypothesis that cyclic adenosine monophosphate (cAMP) signaling contributes to GPER-mediated vasorelaxation. In mesenteric resistance arteries from intact Lewis females, relaxation to 17-β-estradiol (E2; 47±3% of phenylephrine contraction vs. vehicle 89±2%, P<0.001) or G-1 (44±8%, P<0.001) was blunted to a similar extent by denuding (P<0.001) or the nitric oxide synthase inhibitor l-NAME (P<0.001). In contrast, the cyclooxygenase inhibitor indomethacin did not alter vasodilation (P>0.05). The cAMP analog Rp-cAMPS partially attenuated vasodilation (65±7%, P<0.001), while the combination of l-NAME and Rp-cAMPS exhibited additive effects to effectively abolish vasorelaxation (P>0.05 vs. vehicle). Pretreatment of endothelium-intact vessels with the adenylyl cyclase inhibitor SQ (63±6%) or the guanylyl cyclase inhibitor ODQ (62±9%) both partially inhibited the response to G-1 (P<0.01), while pretreatment with the both inhibitors completely abolished vasorelaxation (P>0.05 vs. vehicle). In denuded vessels only SQ reduced the response (88±3%, P<0.001). Moreover, G-1 significantly increased intracellular cAMP levels in cultured mesenteric smooth muscle cells (P<0.05). We conclude that GPER-dependent vasorelaxation apparently involves both endothelial release of nitric oxide which activates guanylyl cyclase and smooth muscle cell activation of adenylyl cyclase. Downstream production of cyclic nucleotides and stimulation of protein kinases may phosphorylate proteins to promote vascular smooth muscle cell relaxation. The ability of GPER to initiate these signaling pathways may contribute to the beneficial vascular effects of estrogen.
Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, United States. Electronic address: lindsey@tulane.edu.
Sarah H
SH
Lindsey
Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, United States.
Liu
L
Liu
Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston-Salem, NC, United States.
Mark C
MC
Chappell
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D003517:Cyclopentanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014664:Vasodilation
C517943:1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone; D003517:Cyclopentanes; C520305:Gper1 protein, rat; D011804:Quinolines; D043562:Receptors, G-Protein-Coupled; D009569:Nitric Oxide; D004958:Estradiol; D000242:Cyclic AMP; D019331:NG-Nitroarginine Methyl Ester
Estrogen; G proteins; GPER; GPR30; Vasodilation; cAMP