Acute impairment of contractile responses by 17<i>β</i>‐estradiol is cAMP and protein kinase G dependent in vascular smooth muscle cells of the porcine coronary arteries

Keung, Wendy; Vanhoutte, Paul M.; Man, Ryk

doi:10.1038/sj.bjp.0706018

Cited by 29 publications

(34 citation statements)

References 41 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: 93%

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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: 93%

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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“…The lack of effects of indomethacin and of inhibitors of adenylyl cyclase (SQ22536) and protein kinase A (KT5720 and Rp-8-Br-cAMP) (30,31) on the hypoxic augmentation rules out the contribution of prostacyclin (37) and the cyclic AMP pathway. Likewise, the combination of TRAM34 and UCL1394 (inhibitors of endothelial Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The emitted fluorescent signal was split by a dichroic beam splitter. The (30,47) Values are means Ϯ SE. Effects of various pharmacological inhibitors or desensitizers on the hypoxic augmentation in contracted (U46619, 3 ϫ 10 Ϫ9 M to 10 Ϫ8 M) porcine coronary arteries with endothelium.…”

Section: To 10mentioning

confidence: 99%

Endothelium-derived NO, but not cyclic GMP, is required for hypoxic augmentation in isolated porcine coronary arteries

Chan¹,

Mak

Gao

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Chan CK, Mak J, Gao Y, Man RY, Vanhoutte PM. Endotheliumderived NO, but not cyclic GMP, is required for hypoxic augmentation in isolated porcine coronary arteries. Am J Physiol Heart Circ Physiol 301: H2313-H2321, 2011. First published October 7, 2011 doi:10.1152/ajpheart.00258.2011.-The present study investigated the mechanism underlying the transient potentiation of vasoconstriction by hypoxia in isolated porcine coronary arteries. Isometric tension was measured in rings with or without endothelium. Hypoxia (PO2 Ͻ30 mmHg) caused a transient further increase in tension (hypoxic augmentation) in contracted (with U46619) preparations. The hypoxic response was endothelium dependent and abolished by inhibitors of nitric oxide synthase [N -nitro-L-arginine methyl ester (L-NAME)] or soluble guanylyl cyclase (ODQ and NS2028). The addition of DETA NONOate (nitric oxide donor) in the presence of L-NAME restored the hypoxic augmentation, suggesting the involvement of the nitric oxide pathway. However, the same was not observed after incubation with 8-bromo-cyclic GMP, atrial natriuretic peptide, or isoproterenol. Assay of the cyclic GMP content showed no change upon exposure to hypoxia in preparations with and without endothelium. Incubation with protein kinase G and protein kinase A inhibitors did not inhibit the hypoxic augmentation. Thus the hypoxic augmentation is dependent on nitric oxide and soluble guanylyl cyclase but independent of cyclic GMP. The hypoxic augmentation persisted in calcium-free buffer and in the presence of nifedipine, ruling out a role for extracellular calcium influx. Hypoxia did not alter the intracellular calcium concentration, as measured by confocal fluorescence microscopy. This observation and the findings that hypoxic augmentation is enhanced by thapsigargin (sarco/endoplasmic reticulum calcium ATPase inhibitor) and inhibited by HA1077 or Y27632 (Rho kinase inhibitors) demonstrate the involvement of calcium sensitization in the phenomenon. soluble guanylyl cyclase; calcium sensitization; nitric oxide ENDOTHELIUM-DEPENDENT AUGMENTATION of contraction by hypoxia has been observed in canine femoral and coronary arteries (10,22,41), in the rat mesenteric artery (57), and in the human coronary artery (56). In the dog, augmented hypoxic coronary vasoconstrictions, which significantly reduce the blood supply to the cardiac muscle, occur in vivo only after previous ischemia-reperfusion injury (41). Considering that the hypoxic augmentation can be repeated consistently even after several episodes of exposure to hypoxia (10), this phenomenon could be important in patients (particularly if they have a previous history of coronary disease) exposed to repeated episodes of reduced oxygen content in the blood, as in the case for example in sleep apnea.The exact mechanism underlying hypoxic endothelium-dependent augmentation of vasoconstriction is not fully understood. Bioassay studies (45) on canine coronary arteries demonstrated that a diffusible substance released by the endothelium contributes to th...

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“…Various phyto-and xenoestrogens also stimulate cAMP production via GPER either in breast cancer cells or in an ER␣-and ER␤-negative cell line [human embryonic kidney (HEK)-293 cells] that was stably transfected with GPER (65,66). Although estrogen-stimulated production of cAMP, a powerful vasodilatory signal, has been demonstrated in rat aortic (15) and porcine coronary artery smooth muscle cells (SMCs) (32), the role of cAMP in response to GPER activation in coronary arteries is unknown. The key component of generating and sustaining vascular tone is the phosphorylation state of the smooth muscle contractile apparatus myosin light chain (MLC) (34).…”

mentioning

confidence: 99%

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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Acute impairment of contractile responses by 17β‐estradiol is cAMP and protein kinase G dependent in vascular smooth muscle cells of the porcine coronary arteries

Cited by 29 publications

References 41 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

Endothelium-derived NO, but not cyclic GMP, is required for hypoxic augmentation in isolated porcine coronary arteries

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

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Acute impairment of contractile responses by 17β‐estradiol is cAMP and protein kinase G dependent in vascular smooth muscle cells of the porcine coronary arteries

Cited by 29 publications

References 41 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

Endothelium-derived NO, but not cyclic GMP, is required for hypoxic augmentation in isolated porcine coronary arteries

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

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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