Abstract 1737: High Pressure Promotes Monocyte Adhesion to the Mouse Vascular Wall Through Induction of VCAM-1, MCP-1, KC and IL-6
Hypertension is a known risk factor for the development of atherosclerosis. We sought to assess how mechanical factors participate to this process. Mouse carotid arteries were maintained in organ culture at normal (80mmHg) or high (150mmHg) intraluminal pressure during 1, 6, 12 or 24 h. Thereafter, fluorescent human monocytes (U937) were injected and allowed to adhere during 30 min before washout. We found that monocyte adhesion was increased in vessels kept at 150mmHg 12h (23.5+5.7 vs 9.9+2.2 cells/mm at 80mmHg; p<0.05) or 24h (26.7+5.7 vs 8.8+1.5 cells/mm; p<0.05). At 24h, high pressure was associated with NF-kappaB activation and increased mRNA expression of MCP-1, IL-6 and VCAM-1 (6.9+2.1, 4.4+0.1 and 2.4+0.1-fold respectively; p<0.05), assessed by quantitative RT-PCR. These results were confirmed by immunohistochemistry, which also revealed an increase in ICAM-1 expression. NF-kappaB inhibition using SN50 peptide abolished the overexpression of MCP-1, IL-6, KC, VCAM-1 and ICAM-1 in vessels kept at 150mmHg, and prevented high pressure-induced monocyte adhesion. Moreover, treatment of vessels and cells with neutralizing antibodies revealed a necessary role for all 3 chemokines (MCP-1, IL-6 and KC) in mechanosensitive monocyte adhesion. Using a similar approach, we found that monocytes bound the vascular wall through interaction of beta1 integrins with VCAM-1 but not ICAM-1. In an in vitro affinity assay using microplates coated with recombinant VCAM-1, we confirmed the additive effect of MCP-1, IL-6 and KC on monocyte adhesion to VCAM-1. Hence, high pressure-induced NF-kappaB promotes monocyte adhesion through the vascular induction of chemokines, which can directly prime monocytes, and increased VCAM-1 expression. These results suggest a pathway through which high blood pressure may directly contribute to the development of atherosclerosis.