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 postischemic 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 wild-type littermate controls were subjected to 1 hour middle cerebral artery occlusion followed by 28-day 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 VEGFA ( vascular endothelial growth factor), FGF2 ( fibroblast growth factor 2), and their receptors VEGFR2 ( vascular endothelial growth factor receptor 2) and FGFR1 ( fibroblast growth factor receptor 1) 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, 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 3'-untranslated regions of those messenger RNAs. CONCLUSIONS: Endothelial miR-15a/16-1 cluster is a negative regulator for postischemic 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.
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Authors | Ping Sun, Kai Zhang, Sulaiman H Hassan, Xuejing Zhang, Xuelian Tang, Hongjian Pu, R Anne Stetler, Jun Chen, Ke-Jie Yin |
Journal | Circulation research
(Circ Res)
Vol. 126
Issue 8
Pg. 1040-1057
(04 10 2020)
ISSN: 1524-4571 [Electronic] United States |
PMID | 32131693
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- MicroRNAs
- Mirn15a microRNA, mouse
- Mirn16 microRNA, mouse
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Topics |
- Animals
- Brain
(metabolism, pathology)
- Endothelium, Vascular
(metabolism, pathology)
- Gene Deletion
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- MicroRNAs
(genetics, metabolism)
- Neovascularization, Physiologic
(physiology)
- Recovery of Function
(physiology)
- Stroke
(genetics, metabolism, pathology)
- Time Factors
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