title: Type VIII collagen mediates vessel wall remodeling after arterial injury and fibrous cap formation in atherosclerosis.
abstract: Collagens in the atherosclerotic plaque signal regulation of cell behavior and provide tensile strength to the fibrous cap. Type VIII collagen, a short-chain collagen, is up-regulated in atherosclerosis; however, little is known about its functions in vivo. We studied the response to arterial injury and the development of atherosclerosis in type VIII collagen knockout mice (Col8(-/-) mice). After wire injury of the femoral artery, Col8(-/-) mice had decreased vessel wall thickening and outward remodeling when compared with Col8(+/+) mice. We discovered that apolipoprotein E (ApoE) is an endogenous repressor of the Col8a1 chain, and, therefore, in ApoE knockout mice, type VIII collagen was up-regulated. Deficiency of type VIII collagen in ApoE(-/-) mice (Col8(-/-);ApoE(-/-)) resulted in development of plaques with thin fibrous caps because of decreased smooth muscle cell migration and proliferation and reduced accumulation of fibrillar type I collagen. In contrast, macrophage accumulation was not affected, and the plaques had large lipid-rich necrotic cores. We conclude that in atherosclerosis, type VIII collagen is up-regulated in the absence of ApoE and functions to increase smooth muscle cell proliferation and migration. This is an important mechanism for formation of a thick fibrous cap to protect the atherosclerotic plaque from rupture.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Joshua
authors.initials: J
authors.lastname: Lopes
authors.forename: Eser
authors.initials: E
authors.lastname: Adiguzel
authors.forename: Steven
authors.initials: S
authors.lastname: Gu
authors.forename: Shu-Lin
authors.initials: SL
authors.lastname: Liu
authors.forename: Guangpei
authors.initials: G
authors.lastname: Hou
authors.forename: Scott
authors.initials: S
authors.lastname: Heximer
authors.forename: Richard K
authors.initials: RK
authors.lastname: Assoian
authors.forename: Michelle P
authors.initials: MP
authors.lastname: Bendeck
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000502:physiology; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D024102:Collagen Type VIII / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004549:Elastin / Q000378:metabolism; D005260:Female; D005263:Femoral Artery / Q000293:injuries; D018093:Gelatinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D009336:Necrosis; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D001057:Apolipoproteins E; D024102:Collagen Type VIII; D012333:RNA, Messenger; D003094:Collagen; D004549:Elastin; D018093:Gelatinases