Lack of α2-antiplasmin promotes re-endothelialization via over-release of VEGF after vascular injury in mice
Lack of α2-antiplasmin promotes re-endothelialization via over-release of VEGF after vascular injury in mice
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DOI：
10.1182/blood-2003-03-0700
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发表时间：
2003-11-15
期刊：
影响因子：
20.3
通讯作者：
Kozawa, O
中科院分区：
文献类型：
--
作者：
Matsuno, H;Ishisaki, A;Kozawa, O
我们在此报道，与野生型小鼠相比，缺乏α2-抗纤溶酶的小鼠（α2-AP(-/-)小鼠）内皮损伤后动脉血流得到良好维持。此外，α2-AP(-/-)小鼠损伤后4周，新内膜的发育显着减少。组织学观察显示，α2-AP(-/-) 小鼠修复后的内皮细胞迅速恢复，增殖指数更高。 α2-AP(-/-)小鼠移植的血管平滑肌细胞(SMC)分泌的血管内皮生长因子(VEGF)的量显着增加。在使用人内皮细胞 (EC) 系的单独实验中，我们可以证明纤溶酶原与 EC 结合，并且这种结合可以被 alpha2-AP 阻止。最后，注射抗 VEGF 受体 1 抗体或 α2-AP 会减少内皮迅速愈合。 α2-AP 是纤溶酶的主要灭活剂，它裂解细胞外基质结合的 VEGF，释放可扩散的蛋白水解片段。因此，α2-AP 的缺乏可能导致损伤区域持续活跃的纤溶酶导致 VEGF 局部过度释放，从而导致血管损伤后迅速重新内皮化。我们的结果为 alpha2-AP 和 VEGF 在血管损伤后再内皮化的发病机制中的作用提供了新的见解。
We here report that the arterial blood flow after endothelial injury in mice deficient in alpha2-antiplasmin (alpha2-AP(-/-) mice) was well maintained compared with that of wild-type mice. Moreover, the development of neointima 4 weeks after injury in alpha2-AP(-/-) mice was significantly decreased. Histologic observations showed a prompt recovery of endothelial cells with a much higher proliferating index in repaired endothellum in alpha2-AP(-/-) mice. The amount of secreted vascular endothelial growth factor (VEGF) by explanted vascular smooth muscle cells (SMCs) from alpha2-AP(-/-) mice was significantly increased. In separate experiments using a human endothelial cell (EC) line, we could demonstrate that plasminogen binds to ECs and that this binding can be prevented by alpha2-AP. Finally, an injection of either an anti-VEGF receptor-1 antibody or alpha2-AP reduced the prompt endothelial healing alpha2-AP is the main inactivator of plasmin, which cleaves extracellular matrix-bound VEGF to release a diffusible proteolytic fragment. Lack of alpha2-AP, therefore, could lead to a local over-release of VEGF by the continuously active plasmin in the injured area, which could result in a prompt re-endothelialization after vascular injury. Our results provide new insight into the role of alpha2-AP and VEGF in the pathogenesis of re-endothelialization following vascular injury.