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Glycine attenuates cerebrovascular remodeling via glycine receptor alpha 2 and vascular endothelial growth factor receptor 2 after stroke.

ABSTRACT: As a dual-acting neurotransmitter, glycine plays critical roles in cerebral ischemia by activating both glycine receptors (GlyRs) and N-methyl-D-aspartate acid receptors (NMDARs). However, the involvement of glycine receptor alpha 2 (GlyRa2) in cerebral ischemia has not been explored. The objective of this study was to determine the mechanism of action of GlyRa2 in cerebrovascular remodeling. After induction of rat tMCAO, levels of the GLRA2 gene and GlyRa2 protein were examined using q-PCR, western blot, and immunohistochemical analyses. Blood-brain barrier permeability, and the presence of hemorrhage and arteriosclerosis were also analyzed. The underlying mechanism of vascular remodeling was examined using immunohistochemical and immunofluorescence analyses. Both the GLRA2 gene and GlyRa2 protein were altered sharply after stroke. GlyRa2 of vascular origin appears to play a protective role after glycine treatment for ischemia. Blockade of GlyRa2 by the addition of cyclothiazide was found to abolish previous improvements in cerebrovascular survival after glycine treatment for tMCAO in rats. GlyRa2-dependent neurovascular remodeling was found to be correlated with the vascular endothelial growth factor receptor 2 (VEGFR2) pathways. These results suggest that vascular-derived GlyRa2 protects against post-ischemic injury. Vascular protection via GlyRa2 is due to VEGFR2/pSTAT3 signaling.

SUBMITTER: Chen Z

PROVIDER: S-EPMC7653569 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Glycine attenuates cerebrovascular remodeling via glycine receptor alpha 2 and vascular endothelial growth factor receptor 2 after stroke.

Chen Zheng Z Wang Xiang X Liao Haikang H Sheng Tao T Chen Panhong P Zhou Hongchang H Pan Yongliang Y Liu Weiqin W Yao Hua H

American journal of translational research 20201015 10

As a dual-acting neurotransmitter, glycine plays critical roles in cerebral ischemia by activating both glycine receptors (GlyRs) and N-methyl-D-aspartate acid receptors (NMDARs). However, the involvement of glycine receptor alpha 2 (GlyRa2) in cerebral ischemia has not been explored. The objective of this study was to determine the mechanism of action of GlyRa2 in cerebrovascular remodeling. After induction of rat tMCAO, levels of the <i>GLRA2</i> gene and GlyRa2 protein were examined using q-P ...[more]

PMID: 33194080

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Project description:Atrial fibrillation (AF) is the most common arrhythmia and is associated with inflammation. AF patients have elevated levels of inflammatory cytokines known to promote vascular leak, such as vascular endothelial growth factor A (VEGF). However, the contribution of vascular leak and consequent cardiac edema to the genesis of atrial arrhythmias remains unknown. Previous work suggests that interstitial edema in the heart can acutely promote ventricular arrhythmias by disrupting ventricular myocyte intercalated disk (ID) nanodomains rich in cardiac sodium channels (NaV1.5) and slowing cardiac conduction. Interestingly, similar disruption of ID nanodomains has been identified in atrial samples from AF patients. Therefore, we tested the hypothesis that VEGF-induced vascular leak can acutely increase atrial arrhythmia susceptibility by disrupting ID nanodomains and slowing atrial conduction. Treatment of murine hearts with VEGF (30-60 min, at clinically relevant levels) prolonged the electrocardiographic P wave and increased susceptibility to burst pacing-induced atrial arrhythmias. Optical voltage mapping revealed slower atrial conduction following VEGF treatment (10?±?0.4 cm/s vs. 21?±?1 cm/s at baseline, p?<?0.05). Transmission electron microscopy revealed increased intermembrane spacing at ID sites adjacent to gap junctions (GJs; 64?±?9 nm versus 17?±?1 nm in controls, p?<?0.05), as well as sites next to mechanical junctions (MJs; 63?±?4 nm versus 27?±?2 nm in controls, p?<?0.05) in VEGF-treated hearts relative to controls. Importantly, super-resolution microscopy and quantitative image analysis revealed reorganization of NaV1.5 away from dense clusters localized near GJs and MJs to a more diffuse distribution throughout the ID. Taken together, these data suggest that VEGF can acutely predispose otherwise normal hearts to atrial arrhythmias by dynamically disrupting NaV1.5-rich ID nanodomains and slowing atrial conduction. These data highlight inflammation-induced vascular leak as a potential factor in the development and progression of AF.

Dataset Information

Glycine attenuates cerebrovascular remodeling via glycine receptor alpha 2 and vascular endothelial growth factor receptor 2 after stroke.

Publications

Glycine attenuates cerebrovascular remodeling via glycine receptor alpha 2 and vascular endothelial growth factor receptor 2 after stroke.

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