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Hypertension is a known risk factor for the development of atherosclerosis. However, how mechanical factors participate to this process is not well understood. We hypothesized that pressure could increase monocyte adhesion, a key feature of atherosclerotic lesion development. C57/bl6 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 monocytic cells (U937) were injected and allowed to adhere during 30 min before washout. We found that monocyte adhesion was increased in vessels at 150mmHg from 12h (23.5±5.7 vs 9.9±2.2 cells/mm at 80mmHg; p<0.05) and remained high at 24h (26.7±5.7 vs 8.8±1.5 cells/mm; p<0.05). Pressure-dependent monocyte adhesion was equivalent to that of vessels at 80mmHg stimulated by 24h LPS (18.7±3.5 vs 5.9±1.6 cells/mm untreated; p<0.05). High pressure was associated with 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. Since NF-kB is activated by pressure and can regulate the expression of adhesion molecules and cytokines, some vessels were incubated with an NF-kB inhibitor peptide, SN50. NF-kB inhibition abolished the overexpression of MCP-1, IL-6, VCAM-1 and ICAM-1 in vessels kept at 150mmHg, and prevented the pressure-dependent monocyte adhesion (4.4±1.5 and 8.9±2.0 cells/mm at 80 and 150mmHg respectively; p=0.1). Moreover, in vessels from FVB mice, which have a reduced NF-kB activity and are less atherosclerosis-prone than C57/bl6, pressure failed to induce monocyte adhesion (2.1±0.8 and 2.1±0.6 cells/mm at 80 and 150 mmHg respectively). Thus, pressure-induced NF-kB promotes monocyte adhesion through induction of cytokine and adhesion molecule expression. These results suggest a pathway through which high blood pressure may directly contribute to the development of atherosclerosis.
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J. Vasc. Biol. 42, Sup:2 (2005) p22