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

被引：22

作者：

Moon, Hyo Eun ^{[1
,2
,3
]}

Byun, Kyunghee ^{[4
,5
]}

Park, Hyung Woo ^{[1
,2
,3
]}

Kim, Jin Hyun ^{[6
]}

Hur, Jin ^{[7
]}

Park, Joong Shin ^{[8
]}

Jun, Jong Kwan ^{[8
]}

Kim, Hyo-Soo

Paek, Seung Leal ^{[1
,2
,3
,9
]}

Kim, In Keyoung ^{[1
]}

Hwang, Jae Ha ^{[1
]}

Kim, Jin Wook ^{[1
]}

Kim, Dong Gyu ^{[1
]}

Sung, Young Chul ^{[10
]}

Koh, Gou-Young ^{[11
]}

Song, Chang W. ^{[12
]}

Lee, Bonghee ^{[4
,5
]}

Paek, Sun Ha ^{[1
,2
,3
]}

机构：

[1] Seoul Natl Univ, Coll Med, Dept Neurosurg, Seoul 110744, South Korea

[2] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110744, South Korea

[3] Seoul Natl Univ, Coll Med, Ischem Hypox Dis Inst, Seoul 110744, South Korea

[4] Gachon Univ, Ctr Regenerat Med, Lee Gil Ya Canc & Diabet Inst, Incheon 406840, South Korea

[5] Gachon Univ, Med Sch, Dept Anat & Cell Biol, Incheon 406840, South Korea

[6] Gyeongsang Natl Univ Hosp, Clin Res Inst, Jinju 660702, South Korea

[7] Seoul Natl Univ Hosp, IRICT, Seoul, South Korea

[8] Seoul Natl Univ Hosp, Dept Obstet & Gynecol, Seoul 110744, South Korea

[9] Mayo Clin, Dept Neurosurg, Rochester, MI USA

[10] Pohang Univ Sci & Technol, Div Mol & Life Sci Integrat Biosci & Biotechnol, Pohang 790784, South Korea

[11] Korea Adv Inst Sci & Technol, Dept Biol Sci, Lab Vasc Biol & Stem Cell, Daejeon 305338, South Korea

[12] Univ Minnesota, Med Sch, Dept Therapeut Radiol Radiat Oncol, Minneapolis, MN 55455 USA

来源：

EXPERIMENTAL NEUROBIOLOGY | 2015年 / 24卷 / 01期

基金：

新加坡国家研究基金会;

关键词：

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

D O I：

10.5607/en.2015.24.1.55

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 a nu beta 3, alpha 4, beta 1, finally leading to migration of EPCs. AKT recruited mTOR, SDF-1, and HIF-1a 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.

引用

页码：55 / 70

页数：16

共 45 条

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