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Gene delivery of soluble vascular endothelial growth factor receptor-1 (sFlt-1) inhibits intra-plaque angiogenesis and suppresses development of atherosclerotic plaque

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Abstract

Intra-plaque angiogenesis plays an important role in the development of atherosclerotic plaque. Vascular endothelial growth factor (VEGF) is a major initiating factor in this pathologic progress. One selective and specific inhibitor of VEGF is soluble VEGF receptor-1 (sFlt-1). The anti-angiogenic utilization of sFlt-1 in treatment of atherosclerotic plaque has not been fully confirmed yet. Our study was designed to construct eukaryotic expression recombinant pEGFP-N1-sFlt-1, evaluate sFlt-1 recombinant’s effects on endothelial cells proliferation and tube formation in vitro, and investigate effects of local high-expressed sFlt-1 on atherosclerotic plaque in vivo. Rabbit models of atherosclerotic plaque were established by high-lipid diet combined with injury induced by balloon catheter on iliac artery intima. Animals were divided into four groups randomly: control group (C), atherosclerotic plaque group (AP), atherosclerotic plaque with blank vector pEGFP-N1 transfection group (APV), and atherosclerotic plaque with pEGFP-N1-sFlt-1 transfection group (APsFlt-1). The local expression of sFlt-1 protein in target artery was detected by western blotting. The plaque area (PA), plaque circumference (PC), and maximum plaque thickness (MPT) were measured via HE staining. Degree of intra-plaque angiogenesis was evaluated by CD34+ cells immunohistochemistry. As results, we observed that pEGFP-N1-sFlt-1 transfection suppressed the HUVECs proliferation and ability of tube formation, against the effect of VEGF. We obtained higher local expression of sFlt-1 protein in Group APsFlt-1 than that in other groups (P < 0.05). PA, PC, and MPT of plaque in group APsFlt-1 were significantly decreased when compared with other groups (P < 0.05). Amount of annulations surrounded by CD34-positive cells was significantly decreased in pEGFP-N1-sFlt-1 transfection group, which represented decreased level of intra-plaque neovessels formation. The present study confirmed that local gene delivery of sFlt-1 can suppress plaque formation, as one of possible mechanisms, via inhibitive effect on intra atherosclerotic plaque angiogenesis, which hints at the clinical utility of sFlt-1 in atherosclerosis therapy.

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Acknowledgments

We gratefully acknowledge the financial support awarded by National Key Technology R&D Program (No.2008BA168B00) and support from Health Department of Jiangxi Province Government, P.R. China. We thank for the advices in manuscript writing given by Dr. Shuhong Li from Toronto General Hospital (Ontario, Canada).

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Authors and Affiliations

  1. Department of Cardiovascular Disease, Second Affiliated Hospital, Nanchang University, 1 MinDe Street, 330006, Nanchang, Jiangxi Province, People’s Republic of China

    Yaosheng Wang, Yihua Zhou, Lipeng He, Kui Hong, Hai Su, Yanqing Wu, Qinghua Wu & Xiaoshu Cheng

  2. Heart Institute of Nanchang University, 330006, Nanchang, People’s Republic of China

    Yaosheng Wang, Kui Hong, Hai Su, Yanqing Wu, Qinghua Wu & Xiaoshu Cheng

  3. Jiangxi Key Lab of Molecular Medicine, Second Affiliated Hospital, Nanchang University, 1 MinDe Street, 330006, Nanchang, Jiangxi Province, People’s Republic of China

    Kui Hong & Xiaoshu Cheng

  4. Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada

    Mihan Han

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  1. Yaosheng Wang
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Correspondence to Xiaoshu Cheng.

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Wang, Y., Zhou, Y., He, L. et al. Gene delivery of soluble vascular endothelial growth factor receptor-1 (sFlt-1) inhibits intra-plaque angiogenesis and suppresses development of atherosclerotic plaque. Clin Exp Med 11, 113–121 (2011). https://doi.org/10.1007/s10238-010-0112-7

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  • DOI: https://doi.org/10.1007/s10238-010-0112-7

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