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G protein-coupled estrogen receptor agonist improves cerebral microvascular function after hypoxia/reoxygenation injury in male and female rats.

ABSTRACT: BACKGROUND AND PURPOSE:Reduced risk and severity of stroke in adult females are thought to depend on normal levels of endogenous estrogen, which is a known neuro- and vasoprotective agent in experimental cerebral ischemia. Recently, a novel G protein-coupled estrogen receptor (GPER, formerly GPR30) has been identified and may mediate the vasomotor and -protective effects of estrogen. However, the signaling mechanisms associated with GPER in the cerebral microcirculation remain unclear. We investigated the mechanism of GPER-mediated vasoreactivity and also its vasoprotective effect after hypoxia/reoxygenation (H/RO) injury. METHODS:Rat cerebral penetrating arterioles from both sexes were isolated, cannulated, and pressurized. Vessel diameters were recorded by computer-aided videomicroscopy. To investigate vasomotor mechanism of the GPER agonist (G-1), several inhibitors with or without endothelial impairment were tested. Ischemia/reperfusion injury was simulated using H/RO. Vasomotor responses to adenosine triphophate after H/RO were measured with or without G-1 and compared with controls. RESULTS:G-1 produced a vasodilatory response, which was partially dependent on endothelium-derived nitric oxide (NO) but not arachidonic acid cascades and endothelial hyperpolarization factor. Attenuation of G-1-vasodilation by the NO synthase inhibitor and endothelium-impairment were greater in vessels from female than male animals. G-1 treatment after H/RO injury fully restored arteriolar dilation to adenosine triphophate compared with controls. CONCLUSIONS:GPER agonist elicited dilation, which was partially caused by endothelial NO pathway and induced by direct relaxation of smooth muscle cells. Further, GPER agonist restored vessel function of arterioles after H/RO injury and may play an important role in the ability of estrogen to protect the cerebrovasculature against ischemia/reperfusion injury.

SUBMITTER: Murata T

PROVIDER: S-EPMC3923380 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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G protein-coupled estrogen receptor agonist improves cerebral microvascular function after hypoxia/reoxygenation injury in male and female rats.

Murata Takahiro T Dietrich Hans H HH Xiang Chuanxi C Dacey Ralph G RG

Stroke 20130129 3

<h4>Background and purpose</h4>Reduced risk and severity of stroke in adult females are thought to depend on normal levels of endogenous estrogen, which is a known neuro- and vasoprotective agent in experimental cerebral ischemia. Recently, a novel G protein-coupled estrogen receptor (GPER, formerly GPR30) has been identified and may mediate the vasomotor and -protective effects of estrogen. However, the signaling mechanisms associated with GPER in the cerebral microcirculation remain unclear. W ...[more]

PMID: 23362079

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Project description:ObjectiveCardioplegic ischemia-reperfusion and diabetes mellitus are correlated with coronary endothelial dysfunction and inactivation of small conductance calcium-activated potassium channels. Increased reactive oxidative species, such as mitochondrial reactive oxidative species, may contribute to oxidative injury. Thus, we hypothesized that inhibition of mitochondrial reactive oxidative species may protect coronary small conductance calcium-activated potassium channels and endothelial function against cardioplegic ischemia-reperfusion-induced injury.MethodsSmall coronary arteries and endothelial cells from the hearts of mice with and without diabetes mellitus were isolated and examined by using a cardioplegic hypoxia and reoxygenation model to determine whether the mitochondria-targeted antioxidant Mito-Tempo could protect against coronary endothelial and small conductance calcium-activated potassium channel dysfunction. The microvessels or mouse heart endothelial cells were treated with or without Mito-Tempo (0-10 μM) 5 minutes before and during cardioplegic hypoxia and reoxygenation. Microvascular function was assessed in vitro by vessel myography. K+ currents of mouse heart endothelial cells were measured by whole-cell patch clamp. The levels of intracellular cytosolic free calcium (Ca2+) concentration, mitochondrial reactive oxidative species, and small conductance calcium-activated potassium protein expression of mouse heart endothelial cells were measured by Rhod-2 fluorescence staining, MitoSox, and Western blotting, respectively.ResultsCardioplegic hypoxia and reoxygenation significantly attenuated endothelial small conductance calcium-activated potassium channel activity, caused calcium overload, and increased mitochondrial reactive oxidative species of mouse heart endothelial cells in both the nondiabetic and diabetes mellitus groups. In addition, treating mouse heart endothelial cells with Mito-Tempo (10 μM) reduced cardioplegic hypoxia and reoxygenation-induced Ca2+ and mitochondrial reactive oxidative species overload in both the nondiabetic and diabetes mellitus groups, respectively (P < .05). Treatment with Mito-Tempo (10 μM) significantly enhanced coronary relaxation responses to adenosine 5'-diphosphate and NS309 (P < .05), and endothelial small conductance calcium-activated potassium channel currents in both the nondiabetic and diabetes mellitus groups (P < .05).ConclusionsAdministration of Mito-Tempo improves endothelial function and small conductance calcium-activated potassium channel activity, which may contribute to its enhancement of endothelium-dependent vasorelaxation after cardioplegic hypoxia and reoxygenation.

Project description:BackgroundEstrogen is formed by the enzyme aromatase (CYP19A1) and signals via three identified receptors ERα (ESR1), ERß (ESR2), and the G protein-coupled estrogen receptor (GPER). Understanding the relative contribution of each receptor to estrogenic signaling may elucidate the disparate effects of this sex hormone across tissues, and recent developments in PCR technology allow absolute quantification and direct comparison of multiple targets. We hypothesized that this approach would reveal tissue- and sex-specific differences in estrogen receptor mRNA.MethodsESR1, ESR2, GPER, and CYP19A1 were measured in four cardiovascular tissues (heart, aorta, kidney, and adrenal gland), three brain areas (somatosensory cortex, hippocampus, and prefrontal cortex), and reproductive tissues (ovaries, mammary gland, uterus, testes) from six male and six female adult Sprague-Dawley rats.ResultsGPER mRNA expression was relatively stable across all tissues in both sexes, ranging from 5.49 to 113 copies/ng RNA, a 21-fold difference. In contrast, ESR1/ESR2 were variable across tissues although similar within an organ system. ESR1 ranged from 4.46 to 614 copies/ng RNA (138-fold difference) while ESR2 ranged from 0.154 to 83.1 copies/ng RNA (540-fold). Significant sex differences were broadly absent except for renal ESR1 (female 206 vs. male 614 copies/ng RNA, P < 0.0001) and GPER (62.0 vs. 30.2 copies/ng RNA, P < 0.05) as well as gonadal GPER (5.49 vs. 47.5 copies/ng RNA, P < 0.01), ESR2 (83.1 vs. 0.299 copies/ng RNA, P < 0.01), and CYP19A1 (322 vs. 7.18 copies/ng RNA, P < 0.01). Cardiovascular tissues showed a predominance of ESR1, followed by GPER. In contrast, GPER was the predominant transcript in the brain with similarly low levels of ESR1 and ESR2. CYP19A1 was detected at very low levels except for reproductive tissues and the hippocampus.ConclusionWhile the data indicates a lack of sex differences in most tissues, significant differences were found in the range of receptor gene expression across tissues as well as in the receptor profile between organ systems. The data provide a guide for future studies by establishing estrogen receptor expression across multiple tissues using absolute PCR quantification. This knowledge on tissue-specific estrogen receptor profiles will aid the development of hormonal therapies that elicit beneficial effects in specific tissues.

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G protein-coupled estrogen receptor agonist improves cerebral microvascular function after hypoxia/reoxygenation injury in male and female rats.

Publications

G protein-coupled estrogen receptor agonist improves cerebral microvascular function after hypoxia/reoxygenation injury in male and female rats.

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