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Circ Res. 2020 Mar 5. doi: 10.1161/CIRCRESAHA.119.315886. [Epub ahead of print]

Endothelium-Targeted Deletion of microRNA-15a/16-1 Promotes Post-Stroke Angiogenesis and Improves Long-Term Neurological Recovery.

Author information

1
Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh School of Medicine.
2
Pittsburgh Institute of Brain Disorders and Recovery, Univerisity of Pittsburgh School of Medicine.

Abstract

Rationale: Angiogenesis promotes neurological recovery after stroke and is associated with longer survival of stroke patients. Cerebral angiogenesis is tightly controlled by certain microRNAs (miRs), such as the miR-15a/16-1 cluster, among others. However, the function of the miR-15a/16-1 cluster in endothelium on post-ischemic cerebral angiogenesis is not known. Objective: To investigate the functional significance and molecular mechanism of endothelial miR-15a/16-1 cluster on angiogenesis in the ischemic brain. Methods and Results: Endothelial cell -selective miR-15a/16-1 conditional knockout (EC-miR-15a/16-1 cKO) mice and WT littermate controls were subjected to 1h middle cerebral artery occlusion (MCAO) followed by 28d reperfusion. Deletion of miR-15a/16-1 cluster in endothelium attenuates post-stroke brain infarction and atrophy, and improves the long-term sensorimotor and cognitive recovery against ischemic stroke. Endothelium-targeted deletion of the miR-15a/16-1 cluster also enhances post-stroke angiogenesis by promoting vascular remodeling and stimulating the generation of newly formed functional vessels, and increases the ipsilateral cerebral blood flow. Endothelial cell-selective deletion of the miR-15a/16-1 cluster up-regulated the protein expression of pro-angiogenic factors vascular endothelial growth factor (VEGFA), fibroblast growth factor 2 (FGF2), and their receptors VEGFR2 and FGFR1 after ischemic stroke. Consistently, lentiviral knockdown of the miR-15a/16-1 cluster in primary mouse or human brain microvascular endothelial cell cultures enhanced in vitro angiogenesis and up-regulated pro-angiogenic proteins expression after oxygen-glucose deprivation (OGD), whereas lentiviral overexpression of the miR-15a/16-1 cluster suppressed in vitro angiogenesis and down-regulated pro-angiogenic proteins expression. Mechanistically, miR-15a/16-1 translationally represses pro-angiogenic factors VEGFA, FGF2, and their receptors VEGFR2 and FGFR1, respectively, by directly binding to the complementary sequences within three prime untranslated regions (3'-UTRs) of those mRNAs. Conclusions: Endothelial miR-15a/16-1 cluster is a negative regulator for post-ischemic cerebral angiogenesis and long-term neurological recovery. Inhibition of miR-15a/16-1 function in cerebrovascular endothelium may be a legitimate therapeutic approach for stroke recovery.

KEYWORDS:

cerebrovascular endothelial cell; miR-15a/16-1

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