Plasmin modulates vascular endothelial growth factor-a-mediated angiogenesis during wound repair
Plasmin modulates vascular endothelial growth factor-a-mediated angiogenesis during wound repair
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DOI：
10.2353/ajpath.2006.050372
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发表时间：
2006-02-01
影响因子：
6
通讯作者：
Eming, SA
中科院分区：
文献类型：
--
作者：
Roth, D;Piekarek, M;Eming, SA
纤溶酶催化的血管内皮生长因子（VEGF）-A同种型VEGF 165的裂解导致其羧基末端肝素结合结构域的损失和其生物活性的显著损失。关于这一过程在体内的意义知之甚少。为了研究VEGF 165的蛋白酶敏感性在伤口愈合中的生物学相关性，我们在伤口愈合受损的遗传小鼠模型（db/db小鼠）中评估了抗纤溶酶蛋白水解的VEGF 165突变体（VEGF 165（A111 P））的活性。在本研究中，我们证明了在该小鼠模型中，纤溶酶活性在伤口部位增加。与野生型VEGF 165相比，突变型VEGF 165在伤口组织裂解物中的稳定性显著增加，从而表明纤溶酶抗性VEGF 165突变体的活性延长。db/db延迟愈合表型可以通过局部应用野生型VEGF 165或VEGF 165（A111 P）来逆转。然而，VEGF 165对纤溶酶裂解的抗性导致在愈合的晚期阶段血管结构的稳定性增加，这是由于血管周围细胞的募集增加以及内皮细胞凋亡的延迟和减少。我们的数据提供了纤溶酶催化裂解调节VEGF 165介导的体内血管生成的第一个迹象。纤溶酶切割位点Arg 110/Ala 111的失活可以在蛋白酶高度活性的条件下（如伤口修复和炎症）保留VEGF 165在治疗性血管生成中的生物学功能。
Plasmin-catalyzed cleavage of the vascular endothelial growth factor (VEGF)-A isoform VEGF165 results in loss of its carboxyl-terminal heparin-binding domain and significant loss in its bioactivity. Little is known about the in vivo significance of this process. To investigate the biological relevance of the protease sensitivity of VEGF165 in wound healing we assessed the activity of a VEGF165 mutant resistant to plasmin proteolysis (VEGF165(A111P)) in a genetic mouse model of impaired wound healing (db/db mouse). in the present study we demonstrate that in this mouse model plasmin activity is increased at the wound site. The stability of the mutant VEGF165 was substantially increased in wound tissue lysates in comparison to wild-type VEGF165, thus indicating a prolonged activity of the plasmin-resistant VEGF165 mutant. The db/db delayed healing phenotype could be reversed by topical application of wild-type VEGF165 or VEGF165(A111P). However, resistance of VEGF165 to plasmin cleavage resulted in the increased stability of vascular structures during the late phase of healing due to increased recruitment of perivascular cells and delayed and reduced endothelial cell apoptosis. Our data provide the first indication that plasmin-catalyzed cleavage regulates VEGF165-mediated angiogenesis in vivo. Inactivation of the plasmin cleavage site Arg110/Ala111 may preserve the biological function of VEGF165 in therapeutic angiogenesis under conditions in which proteases are highly active, such as wound repair and inflammation.