Type VIII collagen mediates vessel wall remodeling after arterial injury and fibrous cap formation in atherosclerosis

Am J Pathol. 2013 Jun;182(6):2241-53. doi: 10.1016/j.ajpath.2013.02.011. Epub 2013 Apr 6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / physiology
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology*
  • Cell Movement / physiology
  • Cell Proliferation
  • Cells, Cultured
  • Collagen / metabolism
  • Collagen Type VIII / deficiency
  • Collagen Type VIII / genetics
  • Collagen Type VIII / physiology*
  • Elastin / metabolism
  • Female
  • Femoral Artery / injuries
  • Gelatinases / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Smooth, Vascular / pathology
  • Necrosis
  • Plaque, Atherosclerotic / metabolism
  • Plaque, Atherosclerotic / pathology*
  • RNA, Messenger / genetics
  • Signal Transduction / physiology
  • Up-Regulation / physiology

Substances

  • Apolipoproteins E
  • Collagen Type VIII
  • RNA, Messenger
  • Collagen
  • Elastin
  • Gelatinases