Mesenchymal stem cells expressing eNOS and a Cav1 mutant inhibit vascular smooth muscle cell proliferation in a rat model of pulmonary hypertension

Haiying Chen, Hongli Yang, Hongmei Yue, Pádraig Michael Strappe, Peng Xia, Li Pan, Yingxin Zhang, Shoudong Chai, Shuangfeng Chen, Longle Ma, Lexin Wang

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    18 Citations (Scopus)

    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.
    Conclusion: 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.
    Original languageEnglish
    Pages (from-to)509-518
    Number of pages10
    JournalHeart Lung and Circulation
    Volume26
    Issue number5
    Early online dateSept 2016
    DOIs
    Publication statusPublished - 01 May 2017

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