Mechanisms by which cleaved kininogen inhibits endothelial cell differentiation and signalling
Mechanisms by which cleaved kininogen inhibits endothelial cell differentiation and signalling
复制标题
DOI：
10.1160/th10-01-0017
复制
发表时间：
2010-11-01
影响因子：
6.7
通讯作者：
Liu, Yuchuan
中科院分区：
文献类型：
--
作者：
Colman, Robert W.;Wu, Yi;Liu, Yuchuan
我们已经证明，切割的高分子量激肽原以浓度依赖性方式抑制内皮细胞管和液泡的形成，这与公认的抗血管生成活性相关。针对尿激酶纤溶酶原激活物受体（uPAR）的抗体模拟切割的激肽原（HKa）对细胞凋亡的抑制作用（HKa 30%和uPAR抗体26%）和管形成在肿瘤血管生成中，癌细胞释放血管生成刺激物如血管内皮生长因子（VEGF）和碱性成纤维细胞生长因子（bFGF），从而刺激内源性前uPA向uPA的转化。然后蛋白水解酶尿激酶纤溶酶原激活物（uPA）与其受体结合，形成与其抑制剂派1的复合物，其导致该复合物的内化并激活细胞外信号调节激酶（ERK）。uPAR的再循环调节内皮细胞（EC）的迁移，ERK的激活促进内皮细胞的迁移和增殖并抑制其凋亡4 HKa破坏uPA uPAR复合物抑制ERK I的激活并阻断uPAR的内化，最终导致细胞死亡和细胞运动停滞，这两者都是血管生成的关键步骤
We have shown that cleaved high molecular weight kininogen inhibits endoththelial cell tube and vacuole formation in a concentration de, pendent manner and this correlates with as recognised anti angiogenic activity The antibody against the urokinase plasminogen activator receptor (uPAR) mimicked the inhibitory effect of cleaved kininogen (HKa) on apoptosis (HKa 30% and uPAR antibody 26%) and tube formation In tumour angiogenesis, cancer cells release angiogenic stimulators such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), thus stimulating the trans formation of endogenous pro uPA to uPA The proteolytic enzyme urokinase plasminogen activator (uPA) then binds to its receptor in a complex with its inhibitor PAI 1, which results in the internalisation of this complex and activates extracellular signal regulated kinase (ERK) Recycling of the uPAR regulates the migration of endothelial cells (ECs), ERK activation stimulates migration and proliferation and suppresses 4 apoptosis of ECs HKa disrupted the uPA uPAR complex inhibited ERK I activation and blocked the internalization of uPAR, eventually resulting in cell death and cell motility arrest Both are critical steps in angiogenesis