Seetharam Divya, Mineo Chieko, Gormley Andrew K, Gibson Linda L, Vongpatanasin Wanpen, Chambliss Ken L, Hahner Lisa D, Cummings Melissa L, Kitchens Richard L, Marcel Yves L, Rader Daniel J, Shaul Philip W
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Circ Res. 2006 Jan 6;98(1):63-72. doi: 10.1161/01.RES.0000199272.59432.5b. Epub 2005 Dec 8.
Vascular disease risk is inversely related to circulating levels of high-density lipoprotein (HDL) cholesterol. However, the mechanisms by which HDL provides vascular protection are unclear. The disruption of endothelial monolayer integrity is an important contributing factor in multiple vascular disorders, and vascular lesion severity is tempered by enhanced endothelial repair. Here, we show that HDL stimulates endothelial cell migration in vitro in a nitric oxide-independent manner via scavenger receptor B type I (SR-BI)-mediated activation of Rac GTPase. This process does not require HDL cargo molecules, and it is dependent on the activation of Src kinases, phosphatidylinositol 3-kinase, and p44/42 mitogen-activated protein kinases. Rapid initial stimulation of lamellipodia formation by HDL via SR-BI, Src kinases, and Rac is also demonstrable. Paralleling the in vitro findings, carotid artery reendothelialization after perivascular electric injury is blunted in apolipoprotein A-I(-/-) mice, and reconstitution of apolipoprotein A-I expression rescues normal reendothelialization. Furthermore, reendothelialization is impaired in SR-BI(-/-) mice. Thus, HDL stimulates endothelial cell migration via SR-BI-initiated signaling, and these mechanisms promote endothelial monolayer integrity in vivo.
血管疾病风险与高密度脂蛋白（HDL）胆固醇的循环水平呈负相关。然而，HDL提供血管保护的机制尚不清楚。内皮单层完整性的破坏是多种血管疾病的一个重要促成因素，而血管病变的严重程度会因内皮修复增强而得到缓解。在此，我们表明HDL在体外通过清道夫受体B1型（SR-BI）介导的Rac GTP酶激活，以一种不依赖一氧化氮的方式刺激内皮细胞迁移。这一过程不需要HDL携带的分子，并且依赖于Src激酶、磷脂酰肌醇3激酶和p44/42丝裂原活化蛋白激酶的激活。HDL通过SR-BI、Src激酶和Rac对片状伪足形成的快速初始刺激也得到了证实。与体外研究结果相似，载脂蛋白A-I（-/-）小鼠在血管周围电损伤后的颈动脉再内皮化受到抑制，而载脂蛋白A-I表达的重建可恢复正常的再内皮化。此外，SR-BI（-/-）小鼠的再内皮化受损。因此，HDL通过SR-BI启动的信号传导刺激内皮细胞迁移，并且这些机制在体内促进内皮单层的完整性。
