Department of Internal Medicine III, Cardiology and Angiology, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
Angiogenesis. 2014 Jan;17(1):27-36. doi: 10.1007/s10456-013-9375-4. Epub 2013 Aug 6.
Diabetic foot ulcers represent a therapeutic problem of high clinical relevance. Reduced vascular supply, neuropathy and diminished expression of growth factors strongly contribute to wound healing impairment in diabetes. Secretoneurin, an angiogenic neuropeptide, has been shown to improve tissue perfusion in different animal models by increasing the amount of vessels in affected areas. Therefore, topical secretoneurin gene therapy was tested in a full thickness wound healing model in diabetic db/db mice. Secretoneurin significantly accelerated wound closure in these mice and immunohistochemistry revealed higher capillary and arteriole density in the wounded area compared to control mice. In-vitro, the mechanism of action of secretoneurin on human dermal microvascular endothelial cells was evaluated in normal and diabetic cells. Secretoneurin shows positive effects on in vitro angiogenesis, proliferation and apoptosis of these cells in a basic fibroblast growth factor dependent manner. A small molecular weight inhibitor revealed fibroblast growth factor receptor 3 as the main receptor for secretoneurin mediated effects. Additionally, we could identify heparan-sulfates as important co-factor of secretoneurin induced binding of basic fibroblast growth factor to human dermal endothelial cells. We suggest topical secretoneurin plasmid therapy as new tool for delayed wound healing in patients suffering from diabetes.
糖尿病足溃疡是一个具有高度临床相关性的治疗难题。血管供应减少、神经病变和生长因子表达减少，极大地导致了糖尿病患者的伤口愈合受损。作为一种血管生成神经肽，分泌素已被证明可通过增加受影响区域的血管数量，改善不同动物模型中的组织灌注。因此，在糖尿病 db/db 小鼠的全层伤口愈合模型中测试了分泌素的局部基因治疗。分泌素显著加速了这些小鼠的伤口闭合，免疫组织化学显示，与对照组小鼠相比，受伤区域的毛细血管和小动脉密度更高。在体外，评估了分泌素对正常和糖尿病人类皮肤微血管内皮细胞的作用机制。在碱性成纤维细胞生长因子依赖性方式下，分泌素对这些细胞的体外血管生成、增殖和凋亡显示出积极作用。小分子抑制剂揭示了成纤维细胞生长因子受体 3 是分泌素介导作用的主要受体。此外，我们还确定了肝素硫酸盐是分泌素诱导的碱性成纤维细胞生长因子与人皮肤内皮细胞结合的重要协同因子。我们建议局部分泌素质粒治疗作为治疗糖尿病患者延迟伤口愈合的新工具。
