title: VEGF-A promotes cardiac stem cell engraftment and myocardial repair in the infarcted heart.
abstract: BACKGROUND
  The objective of this study was to determine whether vascular endothelial growth factor (VEGF)-A subtypes improve cardiac stem cell (CSC) engraftment and promote CSC-mediated myocardial repair in the infarcted heart.
  
  
  METHODS
  CSCs were treated with VEGF receptor (VEGFR) inhibitors, VCAM-1 antibody (VCAM-1-Ab), or PKC-α inhibitor followed by the treatment with VEGF-A. CSC adhesion assays were performed in vitro. In vivo, the PKH26-labeled and VCAM-1-Ab or PKC-α inhibitor pre-treated CSCs were treated with VEGF-A followed by implantation into infarcted rat hearts. The hearts were then collected for measuring CSC engraftment and evaluating cardiac fibrosis and function 3 or 28days after the CSC transplantation.
  
  
  RESULTS
  All three VEGF-A subtypes promoted CSC adhesion to extracellular matrix and endothelial cells. VEGF-A-mediated CSC adhesion required VEGFR and PKCα signaling. Importantly, VEGF-A induced VCAM-1, but not ICAM-1 expression in CSCs through PKCα signaling. In vivo, VEGF-A promoted the engraftment of CSCs in infarcted hearts, which was attenuated by PKCα inhibitor or VCAM-1-Ab. Moreover, VEGF-A-mediated CSC engraftment resulted in a reduction in infarct size and fibrosis. Functional studies showed that the transplantation of the VEGF-A-treated CSCs stimulated extensive angiomyogenesis in infarcted hearts as indicated by the expression of cardiac troponin T and von Willebrand factor, leading to an improved performance of left ventricle. Blockade of PKCα signaling or VCAM-1 significantly diminished the beneficial effects of CSCs treated with VEGF-A.
  
  
  CONCLUSIONS
  VEGF-A promotes myocardial repair through, at least in part, enhancing the engraftment of CSCs mediated by PKCα/VCAM-1 pathway.
authors: Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China; Department of Physiology and Key Lab of human Embryonic Stem Cell of Hubei Province, Hubei University of Medicine, Hubei 442000, China; Center for Medical Research and Department of Physiology, School of Basic Medical Sciences, Wuhan University, Hubei 430071, China. Electronic address: tangjm416@163.com.
authors: Jun-Ming
authors: JM
authors: Tang
authors: Department of Physiology and Key Lab of human Embryonic Stem Cell of Hubei Province, Hubei University of Medicine, Hubei 442000, China.
authors: Bin
authors: B
authors: Luo
authors: Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
authors: Jun-hui
authors: JH
authors: Xiao
authors: Department of Physiology and Key Lab of human Embryonic Stem Cell of Hubei Province, Hubei University of Medicine, Hubei 442000, China.
authors: Yan-xia
authors: YX
authors: Lv
authors: Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
authors: Xiao-lin
authors: XL
authors: Li
authors: Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
authors: Jin-he
authors: JH
authors: Zhao
authors: Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
authors: Fei
authors: F
authors: Zheng
authors: Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
authors: Lei
authors: L
authors: Zhang
authors: Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
authors: Long
authors: L
authors: Chen
authors: Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
authors: Jian-Ye
authors: JY
authors: Yang
authors: Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
authors: Lin-Yun
authors: LY
authors: Guo
authors: Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
authors: Lu
authors: L
authors: Wang
authors: Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
authors: Yu-Wen
authors: YW
authors: Yan
authors: Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
authors: Ya-Mo
authors: YM
authors: Pan
authors: Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
authors: Jia-Ning
authors: JN
authors: Wang
authors: Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
authors: Dong-sheng
authors: DS
authors: Li
authors: Center for Medical Research and Department of Physiology, School of Basic Medical Sciences, Wuhan University, Hubei 430071, China. Electronic address: wanyu@whu.edu.cn.
authors: Yu
authors: Y
authors: Wan
authors: Department of Physiology & Pharmacology, The University of Georgia, Athens, GA 30602, USA.
authors: Shi-You
authors: SY
authors: Chen
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005434:Flow Cytometry / Q000379:methods; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051571:Protein Kinase C-alpha / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000502:physiology; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: C467484:VEGFA protein, human; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D019009:Proto-Oncogene Proteins c-kit; D051571:Protein Kinase C-alpha
keywords: Cardiac stem cells; Myocardial infarction; PKCα; VCAM-1; VEGF-A