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

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 ( mADSC s) and sarpogrelate treatment on aging hindlimb ischemia and the mechanism of action involved. mADSC s (1.0 × 10 7 ) constitutively expressing enhanced green fluorescent protein ( eGFP ) or firefly luciferase ( F luc) reporter were engrafted into the hindlimb of aged V egfr2‐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 mADSC s' survival and therapeutic efficacy against aging hindlimb ischemia. Aged T g( V egfr2‐luc ) mice exhibited decreased inflammatory response, and downregulation of vascular endothelial growth factor ( VEGF )/vascular endothelial growth factor receptor‐2 ( VEGFR 2) compared with young ones following hindlimb ischemia induction, resulting in angiogenesis insufficiency and decompensation for ischemia recovery. Engrafted mADSC s augmented inflammation‐induced angiogenesis to yield pro‐angiogenic/anti‐apoptotic effects partly via the VEGF / VEGFR 2/ mTOR / STAT 3 pathway. Nonetheless, mADSC s displayed limited survival and efficacy following transplantation. Sarpogrelate treatment with mADSC s further upregulated mammalian target of rapamycin ( mTOR )/ STAT 3 signal and modulated pro‐/anti‐inflammatory markers including IL‐1β/ TNF ‐α/ IFN ‐γ and IL ‐6/ IL ‐10, which ultimately facilitated mADSC s' survival and therapeutic benefit in vivo . Sarpogrelate prevented mADSC s from hypoxia/reoxygenation‐induced cell death via a mTOR / STAT 3‐dependent pathway in vitro . This study demonstrated a role of in vivo kinetics of VEGFR 2 as a biomarker to evaluate cell‐derived therapeutic angiogenesis in aging. mADSC s and sarpogrelate synergistically restored impaired angiogenesis and inflammation modulatory capacity in aged hindlimb ischemic mice, indicating its therapeutic promise for PAD in the elderly.