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.
- Author:
Hyo Eun MOON
1
;
Kyunghee BYUN
;
Hyung Woo PARK
;
Jin Hyun KIM
;
Jin HUR
;
Joong Shin PARK
;
Jong Kwan JUN
;
Hyo Soo KIM
;
Seung Leal PAEK
;
In Keyoung KIM
;
Jae Ha HWANG
;
Jin Wook KIM
;
Dong Gyu KIM
;
Young Chul SUNG
;
Gou Young KOH
;
Chang W SONG
;
Bonghee LEE
;
Sun Ha PAEK
Author Information
- Publication Type:In Vitro ; Original Article
- Keywords: COMP-Ang1; angiogenesis; ischemia; Tie2-FAK-AKT pathway
- MeSH: Angiogenesis Inducing Agents; Animals; Blood Vessels; Brain; Brain Injuries*; Brain Ischemia; Capillaries; Cartilage Oligomeric Matrix Protein; Cell Membrane; Cell- and Tissue-Based Therapy; Fetal Blood; Human Umbilical Vein Endothelial Cells; Humans; Integrins; Ischemia; Morphogenesis; Rats; Salvage Therapy; Stem Cells; Wounds and Injuries
- From:Experimental Neurobiology 2015;24(1):55-70
- CountryRepublic of Korea
- Language:English
- 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.
