title: Mesenchymal Stem Cells Expressing eNOS and a Cav1 Mutant Inhibit Vascular Smooth Muscle Cell Proliferation in a Rat Model of Pulmonary Hypertension.
abstract: BACKGROUND
  This study aimed to investigate the effect of bone marrow derived mesenchymal stem cells (rBMSCs) transduced with lentiviral vectors expressing endothelial nitric oxide synthase (eNOS) and/or a mutant caveolin-1(F92A-Cav1), on the pulmonary haemodynamics and structure in a rat model of pulmonary arterial hypertension (PAH).
  
  
  METHODS
  Pulmonary arterial hypertension was induced with monocrotaline (MCT) in 60 adult male Wistar rats prior to delivery of lentiviral vector transduced rBMSCs expressing Cav1, eNOS and/or F92A-Cav1. Changes in pulmonary haemodynamics, right ventricular hypertrophy index (RVHI), and serum nitric oxide (NO) were evaluated. Ultrastructure changes in lung tissues were observed by transmission electron microscopy. Expression of Kruppel-like factor 4 (KLF4), p53, P21, eNOS, and alpha-smooth muscle actin were evaluated by real time PCR, western blotting or immunohistochemistry.
  
  
  RESULTS
  Treatment of PAH rats with gene modified rBMSCs (eNOS +/- Cav1 F92A) decreased right ventricular systolic pressure and improved pulmonary haemodynamics. The protein of alpha-smooth muscle actin expression was decreased whilst KLF4, p53, P21, eNOS expression, and serum NO concentration was elevated. The survival rate of rats in the treatment groups was also improved, after 35 days of observation.
  
  
  CONCLUSIONS
  Intravenous delivery of rBMSCs expressing eNOS/F92A-Cav1 to PAH rats inhibits pulmonary vascular smooth muscle cell proliferation, and improves pulmonary haemodynamics, vascular remodelling and short-term survival. Activation of KLF4-p53 signalling pathway may be involved in these beneficial effects.
authors: Central Laboratory, and Key Laboratory of Oral and Maxillofacial-Head and Neck Medical Biology, Liaocheng People's Hospital, Liaocheng, China; Liaocheng People's Hospital and Clinical School of Taishan Medical University, Liaocheng, China.
authors: Haiying
authors: H
authors: Chen
authors: Central Laboratory, and Key Laboratory of Oral and Maxillofacial-Head and Neck Medical Biology, Liaocheng People's Hospital, Liaocheng, China.
authors: Hongli
authors: H
authors: Yang
authors: Liaocheng People's Hospital and Clinical School of Taishan Medical University, Liaocheng, China.
authors: Hongmei
authors: H
authors: Yue
authors: School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, Australia.
authors: Pádraig Michael
authors: PM
authors: Strappe
authors: Department of Cardiology, Liaocheng People's Hospital and Affiliated Liaocheng People's Hospital of Shandong University, Liaocheng, China.
authors: Peng
authors: P
authors: Xia
authors: Central Laboratory, and Key Laboratory of Oral and Maxillofacial-Head and Neck Medical Biology, Liaocheng People's Hospital, Liaocheng, China.
authors: Li
authors: L
authors: Pan
authors: Central Laboratory, and Key Laboratory of Oral and Maxillofacial-Head and Neck Medical Biology, Liaocheng People's Hospital, Liaocheng, China.
authors: Yingxin
authors: Y
authors: Zhang
authors: Department of Cardiac Surgery, Liaocheng People's Hospital and Affiliated Liaocheng People's Hospital of Shandong University, Liaocheng, China.
authors: Shoudong
authors: S
authors: Chai
authors: Central Laboratory, and Key Laboratory of Oral and Maxillofacial-Head and Neck Medical Biology, Liaocheng People's Hospital, Liaocheng, China.
authors: Shuangfeng
authors: S
authors: Chen
authors: Department of Cardiology, Liaocheng People's Hospital and Affiliated Liaocheng People's Hospital of Shandong University, Liaocheng, China.
authors: Longle
authors: L
authors: Ma
authors: Department of Cardiology, Liaocheng People's Hospital and Affiliated Liaocheng People's Hospital of Shandong University, Liaocheng, China; School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, Australia. Electronic address: lwang@csu.edu.au.
authors: Lexin
authors: L
authors: Wang
mesh_terms: D064591:Allografts; D019943:Amino Acid Substitution; D000818:Animals; D051242:Caveolin 1 / Q000096:biosynthesis* / Q000235:genetics; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D000090062:Kruppel-Like Factor 4; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D020125:Mutation, Missense; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D014161:Transduction, Genetic
chemical_list: C495537:Cav1 protein, rat; D051242:Caveolin 1; C000715467:KLF4 protein, human; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat
keywords: Bone marrow-derived mesenchymal stem cells; Caveolin-1; Endothelial nitric oxide synthase; Kruppel-like factor 4; Pulmonary arterial hypertension; Ventricular function