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中，有助于动脉粥样硬化的形成。在这项研究中，我们证明，与在单体胶原上培养相比，在聚合胶原上培养的SMC显著抑制依赖于αvβ3的SMC在玻璃连蛋白或骨桥蛋白上的迁移，但不改变在I型胶原或纤维连接蛋白上的迁移。在聚合胶原上培养后，αvβ3整合素聚集在玻璃体粘连蛋白上的局灶性粘连受到抑制，细胞外αvβ3的表达没有明显变化。在单体胶原上培养和玻璃体连接蛋白上接种后，纤溶酶原激活物抑制物-1(PAI-1)与αvβ3共定位，阻断PAI-1抗体抑制SMC迁移。相反，聚合型胶原培养抑制PAI-1的分泌及其在局部粘连处的聚集，而刺激尿液纤溶酶原激活物(UPA)的分泌和uPA受体(UPAR)的表达。外源性纤溶酶原激活物-1蛋白的加入可恢复外源性纤溶酶原激活剂抑制SMC在玻璃体粘连蛋白上的迁移，但潜伏期失活的纤溶酶原激活物-1不能恢复这种抑制作用，而纤溶酶原激活物抑制物-1的作用可被uPA共同作用。最后，活化的纤溶酶原激活物-1而不是潜在失活的纤溶酶原激活物-1与αvβ3整合素共定位，而αvβ3的封闭抗体可抑制平滑肌细胞与纤溶酶原激活物-1的黏附。因此，聚合的胶原可能通过调节αvβ3整合素功能和uPA-uPAR-PAI-1系统来动态调节系膜细胞的迁移反应。

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.