Angiopoietin-1 improves endothelial progenitor cell-dependent neovascularization in diabetic wounds

被引:49
|
作者
Balaji, Swathi [1 ]
Han, Nate [1 ]
Moles, Chad [1 ]
Shaaban, Aimen E. [1 ]
Bollyky, Paul L. [2 ]
Crombleholme, Timothy M. [1 ,3 ,4 ]
Keswani, Sundeep G. [1 ]
机构
[1] Cincinnati Childrens Hosp Med Ctr, Lab Regenerat Wound Healing, Div Pediat Gen Thorac & Fetal Surg, Cincinnati, OH 45229 USA
[2] Stanford Univ, Dept Med, Div Infect Dis, Sch Med, Stanford, CA 94305 USA
[3] Childrens Hosp Colorado, Ctr Childrens Surg, Aurora, CO USA
[4] Univ Colorado, Sch Med, Aurora, CO USA
关键词
RECEPTOR TYROSINE KINASES; GROWTH-FACTOR; VESSEL FORMATION; GENE-TRANSFER; BLOOD; VEGF; ANGIOGENESIS; MOBILIZATION; RECRUITMENT; STEM;
D O I
10.1016/j.surg.2015.06.034
中图分类号
R61 [外科手术学];
学科分类号
摘要
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.
引用
收藏
页码:846 / 856
页数:11
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