title: Pretreatment of mesenchymal stem cells with angiotensin II enhances paracrine effects, angiogenesis, gap junction formation and therapeutic efficacy for myocardial infarction.
abstract: BACKGROUND
  Pretreatment of mesenchymal stem cells (MSCs) with growth factors is reported to be an effective route for improving cell-based therapy of myocardial infarction (MI). Angiotensin II (Ang II) triggers vascular endothelial growth factor (VEGF) synthesis in MSCs. This study aimed to investigate the effects and mechanisms of Ang II pretreatment in enhancing the therapeutic efficacy of MSCs in MI.
  
  
  METHODS
  MSCs and endothelial cells (ECs) were isolated from Sprague-Dawley rats. After pretreated with or without 100 nM of Ang II for 24 h, the MSCs were directly injected into the border zones of the ischemic heart. Cardiac function, fibrosis, infarct size, VEGF expression, angiogenesis, and cell differentiation in the infarcted myocardium were determined after 30 days. The cell apoptosis of MSCs post hypoxia was assessed using flow cytometry. The angiogenic activity of MSCs was analyzed using tube formation assay. The gap junction protein connexin-43 (Cx43) expression was detected.
  
  
  RESULTS
  Compared with the MSC group, pretreatment of MSCs with Ang II resulted in better cardiac function, less cardiac fibrosis, smaller infarct size, and higher expression of VEGF and Von Willebrand Factor in ischemic myocardium, but no promotion of cardiomyocyte-like differentiation of MSCs. Ang II pretreatment enhanced the survival of MSCs and the H9c2 cells surrounding MSCs, and augmented the tube formation of ECs and MSCs. Ang II pretreatment up-regulated the Cx43 expression.
  
  
  CONCLUSIONS
  The pretreatment of MSCs with Ang II improved the outcome of MSC-based therapy for MI via the mechanisms of enhancing the paracrine production of VEGF, angiogenesis, and gap junction formation.
authors.affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pharmacology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pharmacology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pharmacology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pharmacology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Hong-Yi
authors.initials: HY
authors.lastname: Zhu
authors.affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pharmacology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Song
authors.affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pharmacology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Hu
authors.affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pharmacology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pharmacology, Nanjing Medical University, Nanjing, PR China. Electronic address: pharm_qpli@njmu.edu.cn.
authors.forename: Qing-Ping
authors.initials: QP
authors.lastname: Li
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001707:Biopsy, Needle; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D017629:Gap Junctions / Q000502:physiology*; D007150:Immunohistochemistry; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D019172:Transplantation Conditioning / Q000379:methods*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II
keywords: Angiogenesis; Angiotensin II; Mesenchymal stem cells; Myocardial infarction; Pretreatment; Vascular endothelial growth factor