Department of Dermatology, University of Cologne, Cologne, Germany.
J Biol Chem. 2013 Jun 21;288(25):17976-89. doi: 10.1074/jbc.M113.451831. Epub 2013 May 3.
Placental growth factor (PlGF) is a critical mediator of blood vessel formation, yet mechanisms of its action and regulation are incompletely understood. Here we demonstrate that proteolytic processing regulates the biological activity of PlGF. Specifically, we show that plasmin processing of PlGF-2 yields a protease-resistant core fragment comprising the vascular endothelial growth factor receptor-1 binding site but lacking the carboxyl-terminal domain encoding the heparin-binding domain and an 8-amino acid peptide encoded by exon 7. We have identified plasmin cleavage sites, generated a truncated PlGF118 isoform mimicking plasmin-processed PlGF, and explored its biological function in comparison with that of PlGF-1 and -2. The angiogenic responses induced by the diverse PlGF forms were distinct. Whereas PlGF-2 increased endothelial cell chemotaxis, vascular sprouting, and granulation tissue formation upon skin injury, these activities were abrogated following plasmin digestion. Investigation of PlGF/Neuropilin-1 binding and function suggests a critical role for heparin-binding domain/Neuropilin-1 interaction and its regulation by plasmin processing. Collectively, here we provide new mechanistic insights into the regulation of PlGF-2/Neuropilin-1-mediated tissue vascularization and growth.
胎盘生长因子（PlGF）是血管生成的关键介质，但它的作用和调节机制尚未完全阐明。在这里，我们证明了蛋白水解处理调节了 PlGF 的生物学活性。具体来说，我们表明纤溶酶处理 PlGF-2 产生了一种蛋白酶抗性的核心片段，该片段包含血管内皮生长因子受体-1 结合位点，但缺乏编码肝素结合域的羧基末端结构域和由外显子 7 编码的 8 个氨基酸肽。我们已经确定了纤溶酶的切割位点，生成了一种模拟纤溶处理 PlGF 的截断 PlGF118 同工型，并比较了其与 PlGF-1 和 -2 的生物学功能。不同 PlGF 形式诱导的血管生成反应是不同的。虽然 PlGF-2 增加了内皮细胞的趋化性、血管发芽和皮肤损伤后的肉芽组织形成，但这些活性在纤溶消化后被消除。对 PlGF/神经纤毛蛋白-1 结合和功能的研究表明，肝素结合域/神经纤毛蛋白-1 相互作用及其受纤溶处理的调节起着关键作用。总的来说，这里我们提供了对 PlGF-2/神经纤毛蛋白-1 介导的组织血管生成和生长的调控的新的机制见解。
