Molecular Basis of HDL-Mediated Endothelial Cell Migration and Reendothelialization
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Vascular disease risk is inversely related to circulating levels of high density lipoprotein (HDL) cholesterol. The atheroprotective nature of HDL is attributed mainly to its role in reverse cholesterol transport (RCT). However, recent reports of human and animal studies have suggested that the atheroprotective nature of HDL is not sufficiently explained by RCT. Therefore, 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. In these studies 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 following perivascular electric injury is blunted in apolipoprotein A-I null (apoA-I-/-) mice, and reconstitution of apoA-I expression rescues normal reendothelialization. Furthermore, reendothelialization is impaired in SR-BI-/- mice. Thus, HDL stimulates endothelial cell migration via SR-BI-initiated activation of Rac GTPase, and HDL and SR-BI promote reendothelialization in vivo, revealing that signaling by the HDL-SR-BI tandem has a potent beneficial impact on the cardiovascular system.