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.

Differences in genetic signaling, and not mechanical properties of the wall, are linked to ascending aortic aneurysms in fibulin-4 knockout mice

“…Col8a1 is proproliferative (2) and promigratory (33). Upregulation of Col8a1 is found in atherosclerosis (52) and injury (74) models where inflammation is induced, vascular wall remodeling is increased, and SMC proliferation and migration are elevated. Col8a1 upregulation may be involved in the SMC overproliferation and arterial wall thickening in Fbln4 Ϫ/Ϫ mice.…”

Hepatic JAK2 protects against atherosclerosis through circulating IGF-1

“…The full length of the aorta, which included the aortic arch to the iliac bifurcation, was dissected out. The descending aorta was severed from the aortic arch and then opened longitudinally, pinned en face and stained with ORO as previously described (73). Stained aortas were imaged using a CoolPix digital camera (Nikon).…”

Modern view on the structure of the vascular extracellular matrix

“…Type VIII collagen forms fibers that are connected to the elastic fibers in the vascular connective tissue (46). It is composed of two different peptide chains and is first isolated from the cell culture of endothelial cells.…”