• Open Access

Adipose stromal cell and sarpogrelate orchestrate the recovery of inflammation-induced angiogenesis in aged hindlimb ischemic mice

Authors

  • Weiwei Fan,

    1. Department of Cardiology & Molecular Imaging Program, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
    2. Department of Cardiology and Geriatrics, Southeast Hospital Affiliated to Xiamen University, Zhangzhou, Fujian, China
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  • Chengxiang Li,

    1. Department of Cardiology & Molecular Imaging Program, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
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  • Xing Qin,

    1. Department of Cardiology & Molecular Imaging Program, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
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  • Shenxu Wang,

    1. Department of Cardiology & Molecular Imaging Program, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
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  • Hu Da,

    1. Institute of Orthopaedics and Traumatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
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  • Kang Cheng,

    1. Department of Cardiology & Molecular Imaging Program, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
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  • Ri Zhou,

    1. Institute of Orthopaedics and Traumatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
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  • Chao Tong,

    1. State Key Laboratory of Cancer Biology, Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
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  • Xiujuan Li,

    1. Department of Cardiology & Molecular Imaging Program, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
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  • Qingting Bu,

    1. Department of Cardiology & Molecular Imaging Program, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
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  • Congye Li,

    1. Department of Cardiology & Molecular Imaging Program, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
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  • Yaling Han,

    1. Department of Cardiology, Shenyang Northern Hospital, Shenyang, China
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  • Jun Ren,

    Corresponding author
    1. Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY, USA
    • Department of Cardiology & Molecular Imaging Program, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
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  • Feng Cao

    Corresponding author
    • Department of Cardiology & Molecular Imaging Program, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
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Correspondence

Professor Feng Cao, Department of Cardiology & Molecular Imaging Program, Xijing Hospital, Fourth Military Medical University, 127# West Changle Road, Xi'an, Shaanxi 710032, China. Tel.: 86 29 84771024; fax: 86 29 84771170; e-mail: wind8828@gmail.com;

Professor Jun Ren, Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071, USA; e-mail: jren@uwyo.edu

Summary

Aging population displays a much higher risk of peripheral arterial disease (PAD) possibly due to the higher susceptibility, poor prognosis, and fewer therapeutic options. This study was designed to examine the impact of combined multipotent adipose-derived stromal cells (mADSCs) and sarpogrelate treatment on aging hindlimb ischemia and the mechanism of action involved. mADSCs (1.0 × 107) constitutively expressing enhanced green fluorescent protein (eGFP) or firefly luciferase (Fluc) reporter were engrafted into the hindlimb of aged Vegfr2-luc transgenic or FVB/N mice subjected to unilateral femoral artery occlusion, followed by a further administration of sarpogrelate. Multimodality molecular imaging was employed to noninvasively evaluate mADSCs' survival and therapeutic efficacy against aging hindlimb ischemia. Aged Tg(Vegfr2-luc) mice exhibited decreased inflammatory response, and downregulation of vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor-2 (VEGFR2) compared with young ones following hindlimb ischemia induction, resulting in angiogenesis insufficiency and decompensation for ischemia recovery. Engrafted mADSCs augmented inflammation-induced angiogenesis to yield pro-angiogenic/anti-apoptotic effects partly via the VEGF/VEGFR2/mTOR/STAT3 pathway. Nonetheless, mADSCs displayed limited survival and efficacy following transplantation. Sarpogrelate treatment with mADSCs further upregulated mammalian target of rapamycin (mTOR)/STAT3 signal and modulated pro-/anti-inflammatory markers including IL-1β/TNF-α/IFN-γ and IL-6/IL-10, which ultimately facilitated mADSCs' survival and therapeutic benefit in vivo. Sarpogrelate prevented mADSCs from hypoxia/reoxygenation-induced cell death via a mTOR/STAT3-dependent pathway in vitro. This study demonstrated a role of in vivo kinetics of VEGFR2 as a biomarker to evaluate cell-derived therapeutic angiogenesis in aging. mADSCs and sarpogrelate synergistically restored impaired angiogenesis and inflammation modulatory capacity in aged hindlimb ischemic mice, indicating its therapeutic promise for PAD in the elderly.

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