Angiopoietin-1 improves endothelial progenitor cell-dependent neovascularization in diabetic wounds.
Angiopoietin-1 improves endothelial progenitor cell-dependent neovascularization in diabetic wounds.
复制标题
血管生成素1改善糖尿病伤口中的内皮祖细胞依赖性新生血管化。
DOI：
10.1016/j.surg.2015.06.034
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发表时间：
2015-09
期刊：
影响因子：
3.8
通讯作者：
Keswani SG
中科院分区：
文献类型：
--
作者：
Balaji S;Han N;Moles C;Shaaban AF;Bollyky PL;Crombleholme TM;Keswani SG
伤口愈合的糖尿病表型的部分特征是新血管形成受损和内皮祖细胞（EPC）募集不足。血管生成素-1（Angiopoietin-1，Ang-1）是一种有效的骨髓EPCs动员剂。骨髓中EPC动员的机制是由基质金属蛋白酶9（MMP-9）和干细胞因子（SCF）介导的。综上所述，我们假设糖尿病伤口中Ang-1的过表达将募集EPCs并改善新生血管形成和伤口愈合。开发了内皮谱系BM标记的糖尿病小鼠模型以追踪BM衍生的EPCs。对FVBN小鼠进行致死性照射，然后用来自同基因Tie 2/LacZ供体小鼠的BM重建。用链脲佐菌素诱发糖尿病。用Ad-Ang-1、Ad-GFP或PBS处理BM移植（BMT）小鼠的背部伤口。在损伤后第7天，收获伤口并进行分析。在EPC动员缺陷型MMP-9 −/−小鼠中进行了类似的实验，以确定Ang-1的作用是否依赖于EPC。Ang-1的过表达导致糖尿病BMT伤口在第7天显著改善再上皮形成、新血管形成和EPC募集。Ang-1治疗导致血清proMMP-9和SCF水平升高，但对血管内皮生长因子（VEGF）水平无影响。根据我们的FACS结果，与野生型对照组相比，MMP-9 −/−小鼠在创伤后第3天的外周血EPC（CD 34 +/Cd 133 +/Flk 1+）计数显示EPC动员受损。EPC动员救援SCF管理，验证EPC动员不足的机制研究，该模型。在MMP-9 −/−小鼠中，Ad-Ang-1以类似的方式加速上皮再生，但对新血管形成没有影响。我们的研究结果表明，血管紧张素-1管理的结果，在改善新血管生成，这是依赖于EPC的招聘，并有直接影响伤口再上皮化。这些数据可能代表了一种新的策略，以纠正受损的糖尿病新生血管的表型，并可能改善糖尿病伤口愈合。
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 EPC 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. 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 (BMT) mice were treated with Ad-Ang-1, Ad-GFP, or PBS. At day 7 post 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. Overexpression of Ang-1 resulted in significantly improved re-epithelialization, neovascularization, and EPC recruitment in diabetic BMT 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 (VEGF) levels. According to our FACS results, peripheral blood EPC (CD34+/Cd133+/Flk1+) counts at day 3 post wounding showed impaired EPC mobilization in MMP-9 −/− mice, when 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. 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.