Eming Sabine A, Krieg Thomas
Department of Dermatology, University of Cologne, Cologne, Germany.
J Investig Dermatol Symp Proc. 2006 Sep;11(1):79-86. doi: 10.1038/sj.jidsymp.5650016.
Vascular endothelial growth factor-A (VEGF-A) is a crucial mediator of vascular hyperpermeability, angiogenesis, and inflammation, processes intimately involved in tissue repair. Although much emphasis has been placed on understanding the synthesis and stability of VEGF-A mRNA, relatively little attention has been given to the study of the stability and processing of VEGF-A proteins themselves. In recent years, several studies indicated that VEGF-A protein activity is highly controlled through interaction with angiogenic or non-angiogenic mediators. We analyzed mechanisms that might control extracellular VEGF-A processing during wound repair. First, our studies provide evidence that VEGF-A protein is a target of proteases present in the microenvironment of human chronic non-healing wounds. Serine proteases, in particular plasmin cleave VEGF165 and digested VEGF fragments, showed decreased mitogenic activity. Inactivation of the plasmin cleavage site Arg110/Ala111 preserved the structural integrity and increased the angiogenic potency of VEGF165 when tested in an impaired healing mouse model. Secondly, we identified significantly increased levels of the potent VEGF-A inhibitor, the soluble form of the VEGF receptor VEGFR-1 (sVEGFR-1) in non-healing wounds when compared to healing wounds. Wound closure in healing and non-healing wounds correlated significantly with a decline in sVEGFR-1 levels. These observations support the concept that VEGF-A and VEGF-A receptors are important mediators in tissue repair. Further, our data provide mechanisms how VEGF-A-mediated interactions are disturbed during impaired healing.
血管内皮生长因子 -A（VEGF-A）是血管通透性增加、血管生成和炎症的关键介质，这些过程与组织修复密切相关。尽管人们非常重视了解VEGF-A mRNA的合成和稳定性，但对VEGF-A蛋白质本身的稳定性和加工过程的研究相对较少。近年来，多项研究表明，VEGF-A蛋白活性通过与血管生成或非血管生成介质的相互作用受到高度调控。我们分析了伤口修复过程中可能控制细胞外VEGF-A加工的机制。首先，我们的研究提供了证据，表明VEGF-A蛋白是人类慢性不愈合伤口微环境中存在的蛋白酶的作用靶点。丝氨酸蛋白酶，特别是纤溶酶切割VEGF165并消化VEGF片段，其促有丝分裂活性降低。在愈合受损的小鼠模型中进行测试时，纤溶酶切割位点Arg110/Ala111的失活保留了VEGF165的结构完整性并提高了其血管生成能力。其次，我们发现与愈合伤口相比，不愈合伤口中强效VEGF-A抑制剂、VEGF受体VEGFR-1的可溶性形式（sVEGFR-1）的水平显著升高。愈合和不愈合伤口的伤口闭合与sVEGFR-1水平的下降显著相关。这些观察结果支持了VEGF-A和VEGF-A受体是组织修复中的重要介质这一概念。此外，我们的数据提供了在愈合受损过程中VEGF-A介导的相互作用如何受到干扰的机制。
