Exp Neurobiol.  2015 Mar;24(1):55-70. 10.5607/en.2015.24.1.55.

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

Affiliations
  • 1Department of Neurosurgery, Seoul National University College of Medicine, Seoul 110-744, Korea. paeksh@snu.ac.kr
  • 2Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-744, Korea.
  • 3Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-744, Korea.
  • 4Center for Regenerative Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, Korea. bhlee@gachon.ac.kr
  • 5Department of Anatomy and Cell Biology, Gachon University Medical School, Incheon 406-840, Korea.
  • 6Clinical Research Institute, Gyeongsang National University Hospital, Jinju 660-702, Korea.
  • 7Innovative Research Institute for Cell Therapy (IRICT), Seoul National University Hospital, Seoul 110-744, Korea.
  • 8Department of Obstetrics & Gynecology, Seoul National University Hospital, Seoul 110-744, Korea.
  • 9Department of Neurosurgery, Mayo Clinic, USA.
  • 10Division of Molecular and Life Science, Integrative Bioscience & Biotechnology, Pohang University of Science and Technology, Pohang 790-784, USA.
  • 11Laboratory for Vascular Biology and Stem Cell, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-338, Korea.
  • 12Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, USA.

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 alphanubeta3, alpha4, beta1, finally leading to migration of EPCs. AKT recruited mTOR, SDF-1, and HIF-1alpha to induce angiogenesis. Taken together, it is concluded that COMP-Ang1 potentiates the angiogenesis of EPCs and enhances the vascular morphogenesis indicating that combination of EPCs with COMP-Ang1 may be a potentially effective regimen for ischemic brain injury salvage therapy.

Keyword

COMP-Ang1; angiogenesis; ischemia; Tie2-FAK-AKT pathway
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