Gene/Protein
Disease
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Drug
Enzyme
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Target Concepts:
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Query: UMLS:C0917798 (
cerebral ischemia
)
17,036
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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
Rgs5
exhibited larger cerebral infarct size, greater neurological motor deficits, and increased brain edema. In our in vitro models, we observed increased G
q
activity and elevated intracellular Ca
2+
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
q
, 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.
...
PMID:Regulator of G-Protein Signaling 5 Maintains Brain Endothelial Cell Function in Focal Cerebral Ischemia. 3287 43
