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Circulation Research. 2005
Published online before print December 8, 2005, doi: 10.1161/01.RES.0000199272.59432.5b
A more recent version of this article appeared on January 6, 2006
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Submitted on September 21, 2005
Revised on November 22, 2005
Accepted on November 28, 2005

High-Density Lipoprotein Promotes Endothelial Cell Migration and Reendothelialization via Scavenger Receptor-B Type I

Divya Seetharam ; Chieko Mineo ; Andrew K. Gormley ; Linda L. Gibson ; Wanpen Vongpatanasin ; Ken L. Chambliss ; Lisa D. Hahner ; Melissa L. Cummings ; Richard L. Kitchens ; Yves L. Marcel ; Daniel J. Rader ; and Philip W. Shaul *

From the Departments of Pediatrics (D.S., C.M., A.K.G., L.L.G., K.L.C., L.D.H., M.L.C., P.W.S.) and Internal Medicine (W.V., R.L.K.) and the Donald W. Reynolds Cardiovascular Clinical Research Center (W.V.), University of Texas Southwestern Medical Center, Dallas, Tex; Lipoprotein and Atherosclerosis Research Group (Y.L.M.), University of Ottawa Heart Institute, Ottawa, Canada; and the Department of Medicine (D.J.R.), University of Pennsylvania School of Medicine, Philadelphia, Pa.

* To whom correspondence should be addressed. E-mail: philip.shaul{at}utsouthwestern.edu.

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.
Key words: high-density lipoprotein • endothelium • migration




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