Integrin regulation of vascular smooth muscle cell migration

平滑肌细胞（SMC）从血管中层迁移到形成的病变有助于动脉粥样硬化的形成。在这项研究中，我们证明，SMC在聚合胶原上培养，与在单体胶原上培养相比，显著抑制αvβ3依赖性SMC在玻连蛋白或骨桥蛋白上的迁移，但不改变在I型胶原或纤连蛋白上的迁移。在聚合胶原上培养后，在玻连蛋白上的粘着斑中聚集的αvβ3整联蛋白被抑制，而αvβ3的细胞外表达没有显著变化。在单体胶原上培养并在玻连蛋白上铺板后，纤溶酶原激活物抑制剂-1（派-1）与αvβ3共定位，阻断派-1抗体抑制SMC迁移。相比之下，聚合胶原培养抑制派-1分泌及其在局灶性粘连处的积聚，而刺激尿纤溶酶原激活物（uPA）分泌和uPA受体（uPAR）表达。加入外源性派-1蛋白可恢复聚合胶原对SMC在玻连蛋白上迁移的抑制作用，而不受潜在失活派-1的影响，同时加入uPA可阻断派-1的作用，最后活性派-1可与αvβ3整合素共定位，而非潜在失活派-1，αvβ3阻断抗体可抑制SMC与派-1的粘附。因此，聚合胶原似乎通过调节αvβ3整合素功能和uPA-uPAR-派-1系统动态调节SMC迁移反应。

Smooth muscle cell (SMC) migration from the medial layer of vessels into forming lesions contributes to atherogenesis. In this study, we demonstrate that SMC culture on polymerized collagen, in contrast with culture on monomer collagen, significantly inhibits αvβ3-dependent SMC migration on vitronectin or osteopontin, but does not alter migration on type I collagen or fibronectin. After culture on polymerized collagen, αvβ3 integrin clustering in focal adhesions on vitronectin is suppressed without a significant change in extracellular expression of αvβ3. Following culture on monomer collagen and plating on vitronectin, plasminogen activator inhibitor-1 (PAI-1) co-localizes with αvβ3 and a blocking PAI-1 antibody inhibits SMC migration. In contrast, polymerized collagen culture suppresses PAI-1 secretion and its accumulation at focal adhesions, while urinary plasminogen activator (uPA) secretion and uPA receptor (uPAR) expression are stimulated. Suppression of SMC migration on vitronectin by polymerized collagen is restored by addition of exogenous PAI-1 protein but not by latent inactive PAI-1, and the effects of PAI-1 are blocked by co-treatment of the SMC with uPA.Finally active PAI-1, but not latent inactive PAI-1, colocalizes with αvβ3 integrin, and blocking antibody for αvβ3 inhibits SMC adhesion to PAI-1. Thus, polymerized collagen appears to dynamically regulate SMC migratory response through modulation of αvβ3 integrin function and the uPA-uPAR-PAI-1 system.