COMP-Ang1 Potentiates EPC Treatment of Ischemic Brain Injury by Enhancing Angiogenesis Through Activating AKT-mTOR Pathway and Promoting Vascular Migration Through Activating Tie2-FAK Pathway

Experimental Neurobiology
Hyo Eun MoonSun Ha Paek

Abstract

Successful recovery from brain ischemia is limited due to poor vascularization surrounding the ischemic zone. Cell therapy with strong angiogenic factors could be an effective strategy to rescue the ischemic brain. We investigated whether cartilage oligomeric matrix protein (COMP)-Ang1, a soluble, stable and potent Ang1 variant, enhances the angiogenesis of human cord blood derived endothelial progenitor cells (hCB-EPCs) for rescuing brain from ischemic injury. COMP-Ang1 markedly improved the tube formation of capillaries by EPCs and incorporation of EPCs into tube formation with human umbilical vein endothelial cells (HUVECs) upon incubation on matrigel in vitro. COMP-Ang1 stimulated the migration of EPCs more than HUVECs in a scratch wound migration assay. The transplanted EPCs and COMP-Ang1 were incorporated into the blood vessels and decreased the infarct volume in the rat ischemic brain. Molecular studies revealed that COMP-Ang1 induced an interaction between Tie2 and FAK, but AKT was separated from the Tie2-FAK-AKT complex in the EPC plasma membrane. Tie2-FAK increased pp38, pSAPK/JNK, and pERK-mediated MAPK activation and interacted with integrins ανβ3, α4, β1, finally leading to migration of EPCs. AKT recruited mTOR, SD...Continue Reading

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Citations

Apr 14, 2017·Cell Death & Disease·Hsiao-Chi TsaiChih-Hsin Tang
Jul 25, 2019·Chinese Medical Journal·Ling-Bing MengTao Gong
May 23, 2019·Canadian Journal of Physiology and Pharmacology·Dina M KhodeerAmani A Elbaz
Aug 16, 2019·Investigative Ophthalmology & Visual Science·Keith D RochfortPhilip M Cummins

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Methods Mentioned

BETA
density gradient centrifugation
ELISA
middle cerebral artery occlusion
proximity ligation
enzyme-linked immunosorbent assay

Software Mentioned

- Pad Prism
GraphPad
Graph
BlobFinderV3
ImageJ

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