Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1α
Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1α
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DOI：
10.1172/jci29710
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发表时间：
2007-05-01
影响因子：
15.9
通讯作者：
Velazquez, Omaida C.
中科院分区：
文献类型：
--
作者：
Gallagher, Katherine A.;Liu, Zhao-Jun;Velazquez, Omaida C.
内皮祖细胞（EPCs）在血管生成和伤口愈合中是必不可少的，但它们的循环和伤口水平数量在糖尿病中减少。本研究旨在确定糖尿病循环和伤口EPCs缺陷的机制。由于骨髓EPCs的动员是通过eNOS激活发生的，我们假设eNOS激活在糖尿病中受损，这导致EPC动员减少。由于高氧激活NOS在其他组织中，我们调查是否高氧恢复EPC动员糖尿病小鼠通过BM NOS激活。此外，我们研究了糖尿病中EPC归巢受损是由于伤口水平基质细胞衍生因子-1 α（SDF-1 α）降低的假设，SDF-1 α是一种在缺血时介导EPC募集的趋化因子。糖尿病小鼠显示BM eNOS磷酸化受损，循环EPCs减少，皮肤伤口中SDF-1 α表达减少。高氧增加BM NO和循环EPCs，NOS抑制剂N-硝基-L-精氨酸-甲酯抑制其作用。在伤口中给予SDF-1 α逆转了EPC归巢损伤，并且与高氧一起协同增强了EPC动员、归巢和伤口愈合。因此，高氧逆转了糖尿病在EPC动员和SDF-1 α方面的缺陷。逆转糖尿病患者EPC归巢缺陷。我们认为所确定的靶点是新颖的，可以显着推进糖尿病伤口愈合领域。
Endothelial progenitor cells (EPCs) are essential in vasculogenesis and wound healing, but their circulating and wound level numbers are decreased in diabetes. This study aimed to determine mechanisms responsible for the diabetic defect in circulating and wound EPCs. Since mobilization of BM EPCs occurs via eNOS activation, we hypothesized that eNOS activation is impaired in diabetes, which results in reduced EPC mobilization. Since hyperoxia activates NOS in other tissues, we investigated whether hyperoxia restores EPC mobilization in diabetic mice through BM NOS activation. Additionally, we studied the hypothesis that impaired EPC homing in diabetes is due to decreased wound level stromal cell-derived factor-1 alpha (SDF-1 alpha), a chemokine that mediates EPC recruitment in ischemia. Diabetic mice showed impaired phosphorylation of BM eNOS, decreased circulating EPCs, and diminished SDF-1 alpha expression in cutaneous wounds. Hyperoxia increased BM NO and circulating EPCs, effects inhibited by the NOS inhibitor N-nitro-L-arginine-methyl ester. Administration of SDF-1 alpha into wounds reversed the EPC homing impairment and, with hyperoxia, synergistically enhanced EPC mobilization, homing, and wound healing. Thus, hyperoxia reversed the diabetic defect in EPC mobilization, and SDF-1 alpha. reversed the diabetic defect in EPC homing. The targets identified, which we believe to be novel, can significantly advance the field of diabetic wound healing.