Plasminogen activator inhibitor 1 and vitronectin protect against stenosis in a murine carotid artery ligation model
Plasminogen activator inhibitor 1 and vitronectin protect against stenosis in a murine carotid artery ligation model
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DOI：
10.1161/01.atv.0000042231.04318.e6
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发表时间：
2002-12-01
影响因子：
8.7
通讯作者：
Pannekoek, H
中科院分区：
文献类型：
--
作者：
de Waard, V;Arkenbout, EK;Pannekoek, H
我们以前报道过纤溶酶原激活物抑制剂I（PAI-1）在玻连蛋白（VN）存在下，抑制体外凝血酶活性。此外，我们证明了人类动脉粥样硬化斑块中凝血酶、PAI-1和VN的共存，以及凝血酶和PAI-1的活性。在这里，我们表明，PAI-1是一个本地凝血酶抑制剂在vivo.Methods和Results-We小鼠颈动脉结扎模型，以评估PAI-1和VN狭窄的作用，通过使用PAI-1缺陷（PAI-1（-/-））和VN-/-小鼠。结扎导致平滑肌细胞（SMC）丰富的内膜无浸润细胞。我们发现，PAI-1（-/-）和VN-/-小鼠产生一个更大的内膜比野生型小鼠作为更广泛的SMC增殖的结果，证明了细胞计数和染色增殖细胞核antigen.Conclusions-In PAI-1（-/-）小鼠，过度内膜形成的凝血酶特异性抑制剂水蛭素。最后，免疫组化分析显示PAI-1，VN，（前）凝血酶抗原内膜病变。我们的观察结果与PAI-1/VN复合物抑制凝血酶介导的SMC增殖是一致的。
Objective-We previously reported that plasminogen activator inhibitor I (PAI-1), in the presence of vitronectin (VN), inhibits thrombin activity in vitro. Furthermore, we demonstrated in human atherosclerotic plaques the colocalization of thrombin, PAI-1, and VN, as well as activity of thrombin and PAI-1. Here, we show that PAI-1 is a local thrombin inhibitor in vivo.Methods and Results-We used the murine carotid artery ligation model to assess the role of PAI-I and VN in stenosis by using PAI-1-deficient (PAI-1(-/-)) and VN-/- mice. Ligation resulted in a smooth muscle cell (SMC)-rich intima without infiltrating cells. We show that PAI-1(-/-) and VN-/- mice generate a larger intima than wild-type mice as the result of more extensive SMC proliferation, as evidenced by cell counting and staining for proliferating cell-nuclear antigen.Conclusions-In PAI-1(-/-) mice, excessive intima formation is prevented by the thrombin-specific inhibitor hirudin. Finally, immunohistochemical analysis revealed PAI-I, VN, and (pro)thrombin antigen in intimal lesions. Our observations are compatible with inhibition of thrombin-mediated SMC proliferation by PAI-1/VN complexes.