VCAM-1 is critical in atherosclerosis.

is an immunoglobulin-like adhesion molecule expressed on activated endothelial cells (1). VCAM-1 binds to α 4 β 1 integrin, which is consti-tutively expressed on lymphocytes, monocytes, and eosinophils. Interestingly , VCAM-1 can mediate both rolling-type adhesion and firm adhesion , depending on the avidity status of α 4 β 1 integrin (2). Although it is structurally similar to ICAM-1 and other endothelial adhesion molecules, VCAM-1's pattern of regulation is unique. VCAM-1 is not expressed under baseline conditions but is rapidly induced by proatherosclerotic conditions in rabbits (3), mice (4), and humans (5), including in early lesions. Initially, it was unclear whether VCAM-1 was simply a marker for atherogenesis or whether it acts in this disease pathway. Studies with cytokine-activated cultured endothe-lial cells and reconstitution assays with purified recombinant VCAM-1 protein (2) suggested that VCAM-1 could mediate robust adhesion of α 4 β 1-expressing cells, even under shear flow. However, it remained unclear whether this adhesion could occur in vivo in large arteries of atherosclerosis-prone animals or patients. Indirect evidence supporting a path-ogenic role for VCAM-1 came from in vivo assays showing that recruitment of peritoneal macrophages into ather-osclerotic lesion of Apoe –/– mice can be inhibited by an α 4 blocking antibody (6). This was further supported by evidence that chronic application of a small peptide that inhibits ligand binding by α 4 β 1 delays the development of atherosclerosis in mice fed an atherogenic diet (7). However, interpretation of this study was complicated by the fact that activated endothe-lial cells can express a second ligand for α 4 β 1 integrin, alternatively spliced fibronectin containing the CS-1 pep-tide. α 4 β 1-mediated adhesion to fibronectin is blocked by the same peptide, and some cultured endothe-lial cells express only fibronectin but not VCAM-1 (8). Other studies, using perfused carotid arteries harvested from Apoe –/– mice, showed that interactions between α 4 β 1 and VCAM-1 can slow down rolling monocytes (9) and that VCAM-1 promotes monocyte adhesion and accumulation on the vessel wall at sites that are prone to developing atherosclerotic lesions (10). Although highly suggestive, these studies stopped short of providing conclusive evidence for a functional role for VCAM-1. This became possible only in VCAM-1 knockout mice. Because of the suspected importance of VCAM-1 in atherosclerosis and other inflammatory diseases, knockout strategies were devised early (11). However, no or excruciatingly few pups homozygous for the null allele were born, …