Background. The diabetic phenotype of wound healing is in part characterized by impaired neovascularization and deficient endothelial progenitor cell (EPC) recruitment. Angiopoietin-1 (Ang-1) is a potent mobilizer of EPCs from the bone marrow (BM). A suggested mechanism for FPC mobilization from the BM is mediated by matrix metalloproteinase 9 (MMP-9) and stem cell factor (SCF). Taken together, we hypothesized that overexpression of Ang-1 in diabetic wounds will recruit EPCs and improve neovascularization and wound healing Methods. An endothelial lineage BM-labeled murine model of diabetes was developed to track BM-derived EPCs. FVBN mice were lethally irradiated and then reconstituted with BM from syngeneic Tie2/LacZ donor mice. Diabetes was induced with streptozotocin. Dorsal wounds in BM-transplanted mice were treated with Ad-Ang-1, Ad-GFP, or phosphate-buffered saline. At day 7 after injury, wounds were harvested and analyzed. A similar experiment was conducted in EPC mobilization deficient MMP-9-/- mice to determine whether the effects of Ang-1 were EPC-dependent. Results. Overexpression of Ang-1 resulted in greatly improved re-epithelialization, neovascularization, and EPC recruitment in diabetic BM-transplanted wounds at day 7. Ang-1 treatment resulted in increased serum levels of proMMP-9 and SCF but had no effect on vascular endothelial growth factor levels. According to our FAGS results, peripheral blood EPC (CD34(+)/Cd133(+)/Flk1(+)) counts at day 3 after wounding showed impaired EPC mobilization in MA/1P-9-/- mice compared with those of wild-type controls. EPC mobilization was rescued by SCF administration, validating this model for EPC-mobilization deficient mechanistic studies. In MMP-9-/- mice, Ad-Ang-1 accelerated re-epithelialization in a similar manner, but had no effect on neovascularization. Conclusion. Our results show that Ang-1 administration results in improved neovascularization which is dependent on EPC recruitment and has direct effects on wound re-epithelialization. These data may represent a novel strategy to correct the phenotype of impaired diabetic neovascularization and may improve diabetic wound healing.
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Shandong Univ Tradit Med, Jinan, Peoples R ChinaShandong Univ Tradit Med, Jinan, Peoples R China
Wang, Ying
Bi, Hongsheng
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Shandong Univ Tradit Chinese Med, Affiliated Eye Hosp, Jinan, Peoples R China
Key Lab Integrated Tradit Chinese & Western Med P, Jinan, Peoples R ChinaShandong Univ Tradit Med, Jinan, Peoples R China
Bi, Hongsheng
Teng, Da
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Shandong Univ Tradit Med, Jinan, Peoples R ChinaShandong Univ Tradit Med, Jinan, Peoples R China
Teng, Da
Zou, Yingying
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Shandong Univ Tradit Chinese Med, Affiliated Eye Hosp, Jinan, Peoples R ChinaShandong Univ Tradit Med, Jinan, Peoples R China
Zou, Yingying
Pan, Xuemei
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Shandong Univ Tradit Chinese Med, Affiliated Eye Hosp, Jinan, Peoples R ChinaShandong Univ Tradit Med, Jinan, Peoples R China
Pan, Xuemei
Guo, Dadong
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Key Lab Integrated Tradit Chinese & Western Med P, Jinan, Peoples R ChinaShandong Univ Tradit Med, Jinan, Peoples R China
Guo, Dadong
Cui, Yan
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Shandong Univ Tradit Chinese Med, Affiliated Eye Hosp, Jinan, Peoples R China
Key Lab Integrated Tradit Chinese & Western Med P, Jinan, Peoples R ChinaShandong Univ Tradit Med, Jinan, Peoples R China
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Univ S China, Sch Life Sci & Technol, Div Pharmacoprote, Hengyang 421001, Peoples R China
Vanderbilt Univ, Med Ctr, Dept Pediat, Div Neonatol, Nashville, TN 37232 USAUniv S China, Sch Life Sci & Technol, Div Pharmacoprote, Hengyang 421001, Peoples R China
Tuo, Qin-hui
Xiong, Guo-zuo
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Univ S China, Affiliated Hosp 2, Dept Gen Surg, Hengyang 421001, Peoples R ChinaUniv S China, Sch Life Sci & Technol, Div Pharmacoprote, Hengyang 421001, Peoples R China
Xiong, Guo-zuo
Zeng, Heng
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Vanderbilt Univ, Med Ctr, Dept Pediat, Div Neonatol, Nashville, TN 37232 USAUniv S China, Sch Life Sci & Technol, Div Pharmacoprote, Hengyang 421001, Peoples R China
Zeng, Heng
Yu, Hei-di
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Vanderbilt Univ, Med Ctr, Dept Pediat, Div Neonatol, Nashville, TN 37232 USAUniv S China, Sch Life Sci & Technol, Div Pharmacoprote, Hengyang 421001, Peoples R China
Yu, Hei-di
Sun, Shao-wei
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Univ S China, Sch Life Sci & Technol, Div Pharmacoprote, Hengyang 421001, Peoples R ChinaUniv S China, Sch Life Sci & Technol, Div Pharmacoprote, Hengyang 421001, Peoples R China
Sun, Shao-wei
Ling, Hong-yan
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Univ S China, Sch Life Sci & Technol, Div Pharmacoprote, Hengyang 421001, Peoples R ChinaUniv S China, Sch Life Sci & Technol, Div Pharmacoprote, Hengyang 421001, Peoples R China
Ling, Hong-yan
Zhu, Bing-yang
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Univ S China, Sch Life Sci & Technol, Div Pharmacoprote, Hengyang 421001, Peoples R ChinaUniv S China, Sch Life Sci & Technol, Div Pharmacoprote, Hengyang 421001, Peoples R China
Zhu, Bing-yang
Liao, Duan-fang
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Univ S China, Sch Life Sci & Technol, Div Pharmacoprote, Hengyang 421001, Peoples R China
Hunan Univ Chinese Med, Sch Pharm, Dept Tradit Chinese Diagnot, Changsha 410208, Hunan, Peoples R ChinaUniv S China, Sch Life Sci & Technol, Div Pharmacoprote, Hengyang 421001, Peoples R China
Liao, Duan-fang
Chen, Jian-xiong
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Vanderbilt Univ, Med Ctr, Dept Pediat, Div Neonatol, Nashville, TN 37232 USAUniv S China, Sch Life Sci & Technol, Div Pharmacoprote, Hengyang 421001, Peoples R China