A major role for VCAM-1, but not ICAM-1, in early atherosclerosis

TLDR

VCAM‑1 and ICAM‑1 are endothelial adhesion molecules expressed in atherosclerosis‑prone regions that may promote monocyte accumulation in the arterial intima, with ICAM‑1 also expressed more broadly. The authors sought to determine VCAM‑1’s role in atherosclerosis by disrupting its fourth Ig domain to create the Vcam1D4D allele. They generated Vcam1D4D mice, crossed them into an LDL‑R‑null background, and fed littermate pairs a cholesterol‑enriched diet for eight weeks to assess lesion development. Vcam1D4D mice exhibited a significant reduction in early aortic lesion area while cholesterol, lipoprotein profiles, and leukocyte counts remained unchanged, and ICAM‑1 deficiency alone or combined with VCAM‑1 had no effect, indicating VCAM‑1 plays a dominant role in atherosclerosis initiation.

Abstract

VCAM-1 and ICAM-1 are endothelial adhesion molecules of the Ig gene superfamily that may participate in atherogenesis by promoting monocyte accumulation in the arterial intima. Both are expressed in regions predisposed to atherosclerosis and at the periphery of established lesions, while ICAM-1 is also expressed more broadly. To evaluate functions of VCAM-1 in chronic disease, we disrupted its fourth Ig domain, producing the murine Vcam1D4D allele. VCAM-1D4D mRNA and protein were reduced to 2–8% of wild-type allele (Vcam1+) levels but were sufficient to partially rescue the lethal phenotype of VCAM-1–null embryos. After crossing into the LDL receptor–null background, Vcam1+/+ and Vcam1D4D/D4D paired littermates were generated from heterozygous intercrosses and fed a cholesterol-enriched diet for 8 weeks. The area of early atherosclerotic lesions in the aorta, quantified by en face oil red O staining, was reduced significantly in Vcam1D4D/D4D mice, although cholesterol levels, lipoprotein profiles, and numbers of circulating leukocytes were comparable to wild-type. In contrast, deficiency of ICAM-1 either alone or in combination with VCAM-1 deficiency did not alter nascent lesion formation. Therefore, although expression of both VCAM-1 and ICAM-1 is upregulated in atherosclerotic lesions, our data indicate that VCAM-1 plays a dominant role in the initiation of atherosclerosis.