Lipoproteins play a major role in
cardiovascular disease and
atherosclerosis. In the vascular wall, they strongly influence the organization of extracellular matrix. The present study set out to investigate the changes in the extracellular matrix of the vessel wall induced by atherogenic diet, focusing on
type VIII collagen, a vascular
collagen that has not previously been investigated in detail. The influence of
cholesterol diet on the expression, distribution, and deposition of
type VIII collagen was examined in carotid arteries of New Zealand White rabbits. Carotid arteries of rabbits receiving diet supplemented with 1%
cholesterol for 6 weeks and those on the same regimen followed by normal chow for 1 day, 10 days, 5 weeks, and 12 weeks were studied and compared with controls not exposed to the
cholesterol diet. Carotid arteries of normocholesterolemic rabbits contained
type VIII collagen-expressing cells in all layers, with focal accumulations of expressing cells in the subendothelial areas, the outer medial zone, and the adventitia. In response to
cholesterol diet,
type VIII collagen synthesis was reduced in media and adventitia and the distribution patterns changed. Expressing cells were found predominantly in the endothelium, and
type VIII collagen accumulated in the intimal space. Immunogold labeling for electron microscopy revealed that
type VIII collagen in the intima is associated with microfibrils extending from the internal elastic lamina. Withdrawal of
cholesterol resulted in reestablishment of the normal distribution pattern. Northern and Western blot analyses supported the immunoconfocal and in situ hybridization data, demonstrating decreased
type VIII collagen expression in response to
cholesterol diet and progressive recovery to normal levels with time after withdrawal of
cholesterol. Our study demonstrates that
type VIII collagen is modulated in the presence of
cholesterol. The data indicate that
type VIII collagen is specifically remodeled during early experimental
atherosclerosis, implying a role for this extracellular matrix component in neointimal growth.