High-density lipoprotein promotes endothelial cell migration and reendothelialization via scavenger receptor-B type I.
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.
Seetharam
Divya
D
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Mineo
Chieko
C
Gormley
Andrew K
AK
Gibson
Linda L
LL
Vongpatanasin
Wanpen
W
Chambliss
Ken L
KL
Hahner
Lisa D
LD
Cummings
Melissa L
ML
Kitchens
Richard L
RL
Marcel
Yves L
YL
Rader
Daniel J
DJ
Shaul
Philip W
PW
D000818:Animals; D016632:Apolipoprotein A-I / Q000502:physiology; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D051122:Scavenger Receptors, Class B / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000502:physiology; D019061:src-Family Kinases / Q000502:physiology
D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D052250:Nitric Oxide Synthase Type III; D019061:src-Family Kinases; D020744:rac GTP-Binding Proteins