Non-genomic activation of adenylyl cyclase and protein kinase G by 17β-estradiol in vascular smooth muscle of the rat superior mesenteric artery

Keung, Wendy; Chan, Matthew L.Y.; Ho, Eva Y.W.; Vanhoutte, Paul M.; Man, Ryk

doi:10.1016/j.phrs.2011.05.010

Cited by 23 publications

(23 citation statements)

References 42 publications

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“…In the present study, the guanylate cyclase inhibitor ODQ did not reverse ER agonist-induced relaxation or decreased [Ca 21 ] i , suggesting little role of guanylate cyclase/ cGMP/PKG in mediating ER responses in mesenteric microvessels. These findings are consistent with the observations that the reported effect of ODQ or the cGMP inhibitor Rp-8-cGMP on E2-mediated relaxation appeared to be small in the porcine coronary and superior mesenteric artery (Keung et al, 2005(Keung et al, , 2011 and negligible in the canine basilar and internal carotid artery (Ramirez-Rosas et al, 2014). The differences in sensitivity of ER-mediated responses to modulators of cGMP or cAMP could be related to different signaling mechanisms in different species and vascular beds and in large versus resistance microvessels.…”

Section: Discussionsupporting

confidence: 89%

“…Also, G1 stimulated BK Ca activity in intact porcine or human coronary VSM cells, and G1-induced relaxation of endothelium-denuded porcine coronary artery was attenuated by iberiotoxin (Yu et al, 2011 (Lincoln et al, 1990). E2 may stimulate cAMP/PKA or cGMP/PKG in the endothelium-denuded porcine coronary artery (White et al, 1995;Darkow et al, 1997;Teoh and Man, 2000;Keung et al, 2005) and rat mesenteric artery (Keung et al, 2011). Endothelial NO and VSM guanylate cyclase and adenylate cyclase/cAMP/PKA signaling could also mediate G1-induced relaxation of the mesenteric artery of a female Lewis rat (Lindsey et al, 2014) and porcine coronary artery .…”

Section: Discussionmentioning

confidence: 92%

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Estrogen Receptor Subtypes Mediate Distinct Microvascular Dilation and Reduction in [Ca²⁺]_i in Mesenteric Microvessels of Female Rat

Mazzuca

Mata

et al. 2014

J Pharmacol Exp Ther

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Estrogen interacts with estrogen receptors (ERs) to induce vasodilation, but the ER subtype and post-ER relaxation pathways are unclear. We tested if ER subtypes mediate distinct vasodilator and intracellular free Ca 21 concentration ([Ca 21 ] i ) responses via specific relaxation pathways in the endothelium and vascular smooth muscle (VSM). Pressurized mesenteric microvessels from female Sprague-Dawley rats were loaded with fura-2, and the changes in diameter and [Ca 21 ] i in response to 17b-estradiol (E2) (all ERs), PPT (4,49,-pyrazole-1,3,5-triyl]-tris-phenol) (ERa), diarylpropionitrile (DPN) (ERb), and G1 [(6)-1-[(3aR*,4S*,9bS*)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro:3H-cyclopenta(c)quinolin-8-yl]-ethanon] (GPR30) were measured. In microvessels preconstricted with phenylephrine, ER agonists caused relaxation and decrease in [Ca 21 ] i that were with E2 5 PPT . DPN . G1, suggesting that E2-induced vasodilation involves ERa . ERb . GPR30. Acetylcholine caused vasodilation and decreased [Ca 21 ] i , which were abolished by endothelium removal or treatment with the nitric oxide synthase blocker N v -nitro-L-arginine methyl ester (L-NAME) and the K 1 channel blockers tetraethylammonium (nonspecific)

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 92%

Estrogen Receptor Subtypes Mediate Distinct Microvascular Dilation and Reduction in [Ca²⁺]_i in Mesenteric Microvessels of Female Rat

Mazzuca

Mata

et al. 2014

J Pharmacol Exp Ther

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“…Consistent with this notion, a recent study indicated that the classic estrogen receptors ER␣ and ER␤ are colocalized with AC in the caveolae of vascular SMCs from rat mesenteric arteries and that estrogen increases cAMP production locally, not globally, in these cells (31). AKAPs are signaling scaffolds that contribute to cAMP signaling in various aspects.…”

Section: Discussionmentioning

confidence: 74%

G protein-coupled estrogen receptor 1 mediates relaxation of coronary arteries via cAMP/PKA-dependent activation of MLCP

Klussmann

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Yu X, Li F, Klussmann E, Stallone JN, Han G. G proteincoupled estrogen receptor 1 mediates relaxation of coronary arteries via cAMP/PKA-dependent activation of MLCP. Am J Physiol Endocrinol Metab 307: E398 -E407, 2014. First published July 8, 2014 doi:10.1152/ajpendo.00534.2013.-Activation of GPER exerts a protective effect in hypertension and ischemia-reperfusion models and relaxes arteries in vitro. However, our understanding of the mechanisms of GPER-mediated vascular regulation is far from complete. In the current study, we tested the hypothesis that GPER-induced relaxation of porcine coronary arteries is mediated via cAMP/PKA signaling. Our findings revealed that vascular relaxation to the selective GPER agonist G-1 (0.3-3 M) was associated with increased cAMP production in a concentration-dependent manner. Furthermore, inhibition of adenylyl cyclase (AC) with SQ-22536 (100 M) or of PKA activity with either Rp-8-CPT-cAMPS (5 M) or PKI (5 M) attenuated G-1-induced relaxation of coronary arteries preconstricted with PGF2␣ (1 M). G-1 also increased PKA activity in cultured coronary artery smooth muscle cells (SMCs). To determine downstream signals of the cAMP/PKA cascade, we measured RhoA activity in cultured human and porcine coronary SMCs and myosin-light chain phosphatase (MLCP) activity in these artery rings by immunoblot analysis of phosphorylation of myosin-targeting subunit protein-1 (p-MYPT-1; the MLCP regulatory subunit). G-1 decreased PGF2␣-induced p-MYPT-1, whereas Rp-8-CPT-cAMPS prevented this inhibitory effect of G-1. Similarly, G-1 inhibited PGF2␣-induced phosphorylation of MLC in coronary SMCs, and this inhibitory effect was also reversed by Rp-8-CPT-cAMPS. RhoA activity was downregulated by G-1, whereas G36 (GPER antagonist) restored RhoA activity. Finally, FMP-API-1 (100 M), an inhibitor of the interaction between PKA and A-kinase anchoring proteins (AKAPs), attenuated the effect of G-1 on coronary artery relaxation and p-MYPT-1. These findings demonstrate that localized cAMP/PKA signaling is involved in GPER-mediated coronary vasodilation by activating MLCP via inhibition of RhoA pathway.

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“…Thus, the endothelium, a guardian of arterial integrity, represents a promising cellular target for 17β‐estradiol via the activation of ERα 18. Beside the well‐recognized role of nuclear ERα, which regulates target gene transcription (genomic action) through activation functions (AFs) 1 and 2,16, 20 a subpopulation of ERα is present at or near the plasma membrane, where it can elicit rapid, nongenomic, membrane‐initiated steroid signaling (MISS) effects 21, 22, 23, 24, 25…”

Section: Introductionmentioning

confidence: 99%

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

Guivarch

Buscato

Guihot

et al. 2018

JAHA

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BackgroundAlthough estrogen receptor α (ERα) acts primarily as a transcription factor, it can also elicit membrane‐initiated steroid signaling. Pharmacological tools and transgenic mouse models previously highlighted the key role of ERα membrane‐initiated steroid signaling in 2 actions of estrogens in the endothelium: increase in NO production and acceleration of reendothelialization.Methods and ResultsUsing mice with ERα mutated at cysteine 451 (ERaC451A), recognized as the key palmitoylation site required for ERα plasma membrane location, and mice with disruption of nuclear actions because of inactivation of activation function 2 (ERaAF20 = ERaAF2°), we sought to fully characterize the respective roles of nuclear versus membrane‐initiated steroid signaling in the arterial protection conferred by ERα. ERaC451A mice were fully responsive to estrogens to prevent atheroma and angiotensin II–induced hypertension as well as to allow flow‐mediated arteriolar remodeling. By contrast, ERαAF20 mice were unresponsive to estrogens for these beneficial vascular effects. Accordingly, selective activation of nuclear ERα with estetrol was able to prevent hypertension and to restore flow‐mediated arteriolar remodeling.ConclusionsAltogether, these results reveal an unexpected prominent role of nuclear ERα in the vasculoprotective action of estrogens with major implications in medicine, particularly for selective nuclear ERα agonist, such as estetrol, which is currently under development as a new oral contraceptive and for hormone replacement therapy in menopausal women.

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Non-genomic activation of adenylyl cyclase and protein kinase G by 17β-estradiol in vascular smooth muscle of the rat superior mesenteric artery

Cited by 23 publications

References 42 publications

Estrogen Receptor Subtypes Mediate Distinct Microvascular Dilation and Reduction in [Ca²⁺]_i in Mesenteric Microvessels of Female Rat

Estrogen Receptor Subtypes Mediate Distinct Microvascular Dilation and Reduction in [Ca²⁺]_i in Mesenteric Microvessels of Female Rat

G protein-coupled estrogen receptor 1 mediates relaxation of coronary arteries via cAMP/PKA-dependent activation of MLCP

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

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Non-genomic activation of adenylyl cyclase and protein kinase G by 17β-estradiol in vascular smooth muscle of the rat superior mesenteric artery

Cited by 23 publications

References 42 publications

Estrogen Receptor Subtypes Mediate Distinct Microvascular Dilation and Reduction in [Ca2+]i in Mesenteric Microvessels of Female Rat

Estrogen Receptor Subtypes Mediate Distinct Microvascular Dilation and Reduction in [Ca2+]i in Mesenteric Microvessels of Female Rat

G protein-coupled estrogen receptor 1 mediates relaxation of coronary arteries via cAMP/PKA-dependent activation of MLCP

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

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Estrogen Receptor Subtypes Mediate Distinct Microvascular Dilation and Reduction in [Ca²⁺]_i in Mesenteric Microvessels of Female Rat

Estrogen Receptor Subtypes Mediate Distinct Microvascular Dilation and Reduction in [Ca²⁺]_i in Mesenteric Microvessels of Female Rat