Adhesion molecules and atherogenesis

Atherosclerosis is an inflammatory disease of the vessel wall characterized by monocyte infiltration in response to pro-atherogenic factors such as ox idized lipids. Recently, the role of specific adhesion molecules in this pr ocess has been explored. The endothelium overlying atherosclerotic lesions expresses P-selectin and the shoulder regions express vascular cell adhesio n molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), which is also expressed on endothelium in regions not prone to plaque developmen t. Serum levels of soluble P-selectin, ICAM-1 and VCAM-1 are elevated in pa tients with angina pectoris or peripheral atherosclerotic disease. Reconsti tuted in vitro systems using monocytes on cytokine-activated endothelial ce lls under shear flow suggested the involvement of P-selectin, L-selectin, V CAM-1, its ligand, VLA-4 integrin and CD18 integrins. Studies of monocyte a dhesion in isolated perfused carotid arteries harvested from atheroscleroti c (apoE-/-) mice show a predominant involvement of P-selectin and its ligan d P-selectin glycoprotein-1 (PSGL-1) in rolling and of VLA-4 and VCAM-1 in firm adhesion. Consistent with these findings, apoE-/- mice that are also d eficient for P-selectin show significantly reduced atherosclerotic lesion s izes and are almost completely protected from neointimal growth after vascu lar injury. Milder effects are also seen in the low-density lipoprotein (LD L) receptor deficient (LDLR-/-) mouse. In a high cholesterol/ cholate model , a role of ICAM-1 and CD18 integrins was also shown, but this awaits confi rmation in more physiologic models. Transient blockade of the VLA-4/VCAM-1 adhesion pathway by antibodies or peptides in apoE-/- or LDLR-/- mice reduc ed monocyte and lipid accumulation in lesions. These data suggest that P-se lectin, PSGL-1, VLA-4 and VCAM-1 are the most important adhesion molecules involved in monocyte recruitment to atherosclerotic lesions.