Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1α
Katherine A. Gallagher, … , Stephen R. Thom, Omaida C. Velazquez
Katherine A. Gallagher, … , Stephen R. Thom, Omaida C. Velazquez
Published May 1, 2007
Citation Information: J Clin Invest. 2007;117(5):1249-1259. https://doi.org/10.1172/JCI29710.
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Research Article

Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1α

Abstract

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–1α (SDF-1α), a chemokine that mediates EPC recruitment in ischemia. Diabetic mice showed impaired phosphorylation of BM eNOS, decreased circulating EPCs, and diminished SDF-1α 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-1α 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-1α 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.

Authors

Katherine A. Gallagher, Zhao-Jun Liu, Min Xiao, Haiying Chen, Lee J. Goldstein, Donald G. Buerk, April Nedeau, Stephen R. Thom, Omaida C. Velazquez

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Figure 6

Synergistic effect of SDF-1α and HBO on diabetic wound healing.

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Synergistic effect of SDF-1α and HBO on diabetic wound healing. (A) Four...
(A) Four groups of wounded diabetic mice were treated daily with PBS, HBO, SDF-1α, or HBO+SDF-1α. The fraction of initial wound size was measured daily by digital photography and analyzed with ImageJ for 6 days after wounding. Each point represents the mean of 5 experiments. Diabetic mice treated with SDF-1α+HBO had significantly improved wound healing rates at all time points when compared with PBS-treated controls (*P < 0.001 at days 1–5; **P < 0.05 at day 6). Diabetic mice treated with either HBO or SDF-1α demonstrated significantly improved wound healing over PBS controls at days 2, 3, and 5 (#P < 0.05). (B) Representative wounds at days 0, 3, and 6 are shown for each group. (C) Trichrome staining of wound tissues at day 6. Collagen was stained as blue. (D) Quantification of collagen content. Data are based on 5 scanned slides in each group at day 6. Data are based on 3 experiments. SDF-1α+HBO–treated mice demonstrated a significant rise in wound vessel density and collagen deposit compared with individual treatments alone (*P < 0.05), while SDF-1α and HBO treatments alone had significant increases compared with PBS control (**P < 0.05) at day 6. (E) Effect of timing in the initiation of SDF-1α+HBO therapy on wound healing in diabetic mice. Wound closure rates were monitored when treatment was started at days 0, 1, 3, and 5 after wounding and compared with the PBS treated group. Early treatment (days 0 and 1) was necessary to achieve increased closure rate.