VCAM-1 plays a major role in the initiation of atherosclerosis, while ICAM-1 does not. The study used a mouse model with a mutation in the fourth Ig domain of VCAM-1 (Vcam1D4D) to investigate its role in atherosclerosis. These mice showed reduced VCAM-1 expression but were able to survive and reproduce. When crossed into the LDL receptor-null background and fed a cholesterol-enriched diet, Vcam1D4D mice had significantly reduced early atherosclerotic lesions in the aorta compared to wild-type mice, despite similar cholesterol levels, lipoprotein profiles, and leukocyte counts. In contrast, ICAM-1 deficiency alone or in combination with VCAM-1 deficiency did not affect nascent lesion formation. This suggests that VCAM-1 is essential for the initiation of atherosclerosis, while ICAM-1 has a less significant role. The study highlights the importance of VCAM-1 in monocyte recruitment and adhesion to the arterial intima, which is a critical step in atherosclerosis development. The findings indicate that VCAM-1 is a key player in the early stages of atherosclerosis, while ICAM-1 is not as critical.VCAM-1 plays a major role in the initiation of atherosclerosis, while ICAM-1 does not. The study used a mouse model with a mutation in the fourth Ig domain of VCAM-1 (Vcam1D4D) to investigate its role in atherosclerosis. These mice showed reduced VCAM-1 expression but were able to survive and reproduce. When crossed into the LDL receptor-null background and fed a cholesterol-enriched diet, Vcam1D4D mice had significantly reduced early atherosclerotic lesions in the aorta compared to wild-type mice, despite similar cholesterol levels, lipoprotein profiles, and leukocyte counts. In contrast, ICAM-1 deficiency alone or in combination with VCAM-1 deficiency did not affect nascent lesion formation. This suggests that VCAM-1 is essential for the initiation of atherosclerosis, while ICAM-1 has a less significant role. The study highlights the importance of VCAM-1 in monocyte recruitment and adhesion to the arterial intima, which is a critical step in atherosclerosis development. The findings indicate that VCAM-1 is a key player in the early stages of atherosclerosis, while ICAM-1 is not as critical.