Adhesion of monocytes to arterial endothelium and initiation of atherosclerosis are critically dependent on vascular cell adhesion molecule-1 gene dosage.
- Vascular cell adhesion molecule-1 (VCAM-1/Vcam1) is a cytokine-inducible member of the immunoglobulin gene superfamily that is expressed by arterial endothelial cells in regions predisposed to atherosclerosis and at borders of atherosclerotic plaques. To determine whether VCAM-1 expression regulates atherosclerotic lesion formation, we crossed Vcam1 domain 4-deficient (D4D) mice, which partially circumvent the embryonic lethality of Vcam1 null mice, with apolipoprotein E null (Apoe(-/-)) mice, which spontaneously develop hypercholesterolemia and atherosclerosis. In the Apoe(-/-) background, mice homozygous for the Vcam1 D4D allele had markedly reduced arterial VCAM-1 expression, monocyte adherence in the aortic root, and fatty streak formation. Heterozygous Vcam1 D4D mice revealed a Vcam1 gene-dosage effect and had intermediate, yet significant, reductions in these parameters. Our data demonstrate that VCAM-1 plays a pivotal role in the initiation of atherosclerosis in Apoe(-/-) mice.
Dansky
H M
HM
Rockefeller University, New York, NY, and the Toronto General Research Institute (M.I.C.), University of Toronto, Toronto, Ontario, Canada.
Barlow
C B
CB
Lominska
C
C
Sikes
J L
JL
Kao
C
C
Weinsaft
J
J
Cybulsky
M I
MI
Smith
J D
JD
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D018628:Gene Dosage; D018390:Gene Targeting; D006937:Hypercholesterolemia / Q000209:etiology; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics* / Q000502:physiology*
D001057:Apolipoproteins E; D019010:Vascular Cell Adhesion Molecule-1