Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0022116 (
ischemia
)
91,303
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Prolonged occlusion of multiple microvessels causes microvascular injury.
G protein-coupled receptor 124
(
GPR124
) has been reported to be required for maintaining central nervous system (CNS) angiogenesis and blood-brain barrier integrity. However, the molecular mechanisms by which
GPR124
regulates pericytes during
ischemia
have remained elusive.
Methods
: A microsphere embolism-induced
ischemia
model was used to evaluate the expression of
GPR124
following microsphere embolism. Immunocytochemistry and stochastic optical reconstruction microscopy imaging were used to assess the expression and distribution of
GPR124
in human brain vascular pericytes (HBVPs) and after the treatment with 3-morpholino-sydnonimine (SIN-1) or oxygen-glucose deprivation (OGD). The effect of
GPR124
knockdown or overexpression on HBVP migration was analyzed in vitro using wound healing assays and a microfluidic device.
GPR124
loss-of-function studies were performed in HBVPs and HEK293 cells using CRISPR-Cas9-mediated gene deletion. Time-lapse imaging was used to assess dynamic changes in the formation of filopodia in an individual cell. Finally, to explore the functional domains required for
GPR124
activity, deletion mutants were constructed for each of the N-terminal domains.
Results
:
GPR124
expression was increased in pericytes following microsphere embolism. Morphological analysis showed localization of
GPR124
to focal adhesions where
GPR124
bound directly to the actin binding protein vinculin and upregulated Cdc42. SIN-1 or OGD treatment redistributed
GPR124
to the leading edges of HBVPs where
GPR124
signaling was required for pericyte filopodia formation and directional migration. Partial deletion of
GPR124
domains decreased SIN-1-induced filopodia formation and cell migration.
Conclusion
: Taken together, our results provide the first evidence for a role of
GPR124
in pericyte migration under ischemic conditions and suggest that
GPR124
was essential for Cdc42 activation and filopodia formation.
...
PMID:GPR124 facilitates pericyte polarization and migration by regulating the formation of filopodia during ischemic injury. 3153 30
