Vascular endothelial growth factor promotes cardiac stem cell migration via the PI3K/Akt pathway.
VEGF is a major inducer of angiogenesis. However, the homing role of VEGF for cardiac stem cells (CSCs) is unclear. In in vitro experiments, CSCs were isolated from the rat hearts, and a cellular migration assay was performed using a 24-well transwell system. VEGF induced CSC migration in a concentration-dependent manner, and SU5416 blocked this. Western blot analysis showed that the phosphorylated Akt was markedly increased in the VEGF-treated CSCs and that inhibition of pAkt activity significantly attenuated the VEGF-induced the migration of CSCs. In in vivo experiments, rat heart myocardial infarction (MI) was induced by left coronary artery ligation. One week after MI, the adenoviral vector expressing hVEGF165 and LacZ genes were injected separately into the infarcted myocardium at four sites before endomyocardial transplantation of 2x10(5) PKH26 labeled CSCs (50 muL) at atrioventricular groove. One week after CSC transplantation, RT-PCR, immunohistochemical staining, Western blot, and ELISA analysis were performed to detect the hVEGF mRNA and protein. The expression of hVEGF mRNA and protein was significantly increased in the infarcted and hVEGF165 transfected rat hearts, accompanied by an enhanced PI3K/Ak activity, a greater accumulation of CSCs in the infarcted region, and an improvement in cardiac function. The CSC accumulation was inhibited by either the VEGF receptor blocker SU5416 or the PI3K/Ak inhibitor wortmannin. VEGF signaling may mediate the migration of CSCs via activation of PI3K/Akt.
Center for Medical Research and Department of Physiology, School of Basic Medical Sciences, Wuhan university, Hubei 430071, PR China. tangjm416@163.com
Junming
J
Tang
Jianing
J
Wang
Xia
X
Kong
Jianye
J
Yang
Linyun
L
Guo
Fei
F
Zheng
Lei
L
Zhang
Yongzhang
Y
Huang
Yu
Y
Wan
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology / Q000628:therapy
D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019009:Proto-Oncogene Proteins c-kit; D042461:Vascular Endothelial Growth Factor A; C467484:VEGFA protein, human; C467498:vascular endothelial growth factor A, rat