The Protective Effects Of GDF11 On Blood Flow Recovery In Diabetic Hindlimb Ischemic Rats And Its Possible Mechanisms

BackgroundDiabetes mellitus is a common,chronic,metabolic disease with considerable morbidity and mortality.CLI,the most severe form of PAD in which blood flow is not sufficient to maintain tissue viability,is leading cause of incurable ulceration,gangrene,and even lower extremity amputation.Many diabetic individuals with PAD are not candidates for currently available surgical or endovascular procedures due to diffuse vascular disease.Consequently,it is essential for therapeutic interventions aimed at enhancing angiogenesis and restoring blood flow in diabetic CLI.Ischemia-induced vascularization is strongly associated with endothelial progenitor cells(EPCs),which are mobilized from the bone marrow and then home to sites of vascular damage where they contribute to new blood vessel formation and recovery.However,levels and functions of EPCs are dramatically reduced in patients with diabetes.It is believed to be one of the important pathogenesis of vascular complications in diabetes,as manifested by the impaired perfusion recovery.As the member of the transforming growth factor ?(TGF?)superfamily,growth differentiation factor 11(GDF11)plays an important role in mammalian development.Recently,GDF11 has attracted significant attention as a circulating"rejuvenating factor".Some reports have revealed that GDF11 appeared to decline with age,and exogenous administration of GDF11 reverse age-related defects in the skeletal muscle,heart,and cerebral vasculature.However,data regarding GDF11 and vascularization is scarce.Extrapolating from those studies,we hypothesized that GDF11 may play a vital role in peripheral ischemia-induced angiogenesis in diabetes.In the current study,we aimed to investigate whether GDF11 could improve neovascularization in diabetic limb ischemia and to reveal the possible mechanisms involved.Aims The aim of this study was to investigate the effects of GDF11 on angiogenesis in diabetic hindlimb ischemia and its possible mechanisms.MethodsUnilateral hindlimb ischemia was surgically conducted in streptozotocin-induced diabetic rats treated with recombinant GDF11 or citrate buffer,adenovirus encoding GDF11 or GFP,and GDF11 antibody or IgG antibody.For mechanistic studies,endothelial progenitor cells(EPCs)were isolated from rat bone marrow.ResultsHere,we found that systematic replenishment of GDF11 improved vascularization,and subsequently increased blood flow in diabetic rats with hindlimb ischemia.Conversely,anti-GDF11 monoclonal antibody treatment caused impairment of vascularization,and thus decreased' blood flow.Mechanistically,the GDF11-mediated positive effects could be attributed to the activation of transforming growth factor-?2/Smad2/3(TGF-(3/Smad2/3)and protein kinase B/hypoxia induced factor 1?(AKT/HIF1?)pathways.ConclusionOur findings suggest that GDF11 repletion may improve angiogenesis and thus may lead to a new therapeutic approach for diabetic hindlimb ischemia.