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Regulator of G-Protein Signaling 5 Maintains Brain Endothelial Cell Function in Focal Cerebral Ischemia

Journal of the American Heart Association, 2020-09, Vol.9 (18), p.e017533-e017533 [Peer Reviewed Journal]

2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. ;ISSN: 2047-9980 ;EISSN: 2047-9980 ;DOI: 10.1161/JAHA.120.017533 ;PMID: 32875943

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  • Title:
    Regulator of G-Protein Signaling 5 Maintains Brain Endothelial Cell Function in Focal Cerebral Ischemia
  • Author: Sladojevic, Nikola ; Yu, Brian ; Liao, James K
  • Subjects: Animals ; Blood-Brain Barrier - metabolism ; blood‐brain barrier ; Brain Ischemia - metabolism ; Carotid Arteries - metabolism ; cell signaling ; Disease Models, Animal ; Endothelium, Vascular - metabolism ; ischemic stroke ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nitric Oxide Synthase Type III - metabolism ; Original Research ; Receptors, AMPA - metabolism ; Receptors, AMPA - physiology ; RGS Proteins - metabolism ; RGS Proteins - physiology ; vascular biology
  • Is Part Of: Journal of the American Heart Association, 2020-09, Vol.9 (18), p.e017533-e017533
  • Description: Background Regulator of G-protein signaling 5 (RGS5) is a negative modulator of G-protein-coupled receptors. The role of RGS5 in brain endothelial cells is not known. We hypothesized that RGS5 in brain microvascular endothelial cells may be an important mediator of blood-brain barrier function and stroke severity after focal cerebral ischemia. Methods and Results Using a transient middle cerebral artery occlusion model, we found that mice with global and endothelial-specific deletion of exhibited larger cerebral infarct size, greater neurological motor deficits, and increased brain edema. In our in vitro models, we observed increased G activity and elevated intracellular Ca levels in brain endothelial cells. Furthermore, the loss of endothelial RGS5 leads to decreased endothelial NO synthase expression and phosphorylation, relocalization of endothelial tight junction proteins, and increased cell permeability. Indeed, RGS5 deficiency leads to increased Rho-associated kinase and myosin light chain kinase activity, which were partially reversed in our in vitro model by pharmacological inhibition of G , metabotropic glutamate receptor 1, and ligand-gated ionotropic glutamate receptor. Conclusions Our findings indicate that endothelial RGS5 plays a novel neuroprotective role in focal cerebral ischemia. Loss of endothelial RGS5 leads to hyperresponsiveness to glutamate signaling pathways, enhanced Rho-associated kinase- and myosin light chain kinase-mediated actin-cytoskeleton reorganization, endothelial dysfunction, tight junction protein relocalization, increased blood-brain barrier permeability, and greater stroke severity. These findings suggest that preservation of endothelial RGS5 may be an important therapeutic strategy for maintaining blood-brain barrier integrity and limiting the severity of ischemic stroke.
  • Publisher: England: John Wiley and Sons Inc
  • Language: English
  • Identifier: ISSN: 2047-9980
    EISSN: 2047-9980
    DOI: 10.1161/JAHA.120.017533
    PMID: 32875943
  • Source: GFMER Free Medical Journals
    MEDLINE
    PubMed Central
    Wiley Online Library Open Access
    ROAD: Directory of Open Access Scholarly Resources
    DOAJ Directory of Open Access Journals
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