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Arterioscler. Thromb. Vasc. Biol. · Mar 2007
Vascular endothelial growth factor synergistically enhances induction of E-selectin by tumor necrosis factor-alpha.
- Anita K Stannard, Rohit Khurana, Ian M Evans, Vassiliki Sofra, David I R Holmes, and Ian Zachary.
- BHF Laboratories, Department of Medicine, The Rayne Building, University College London, 5 University Street, London WC1E 6JJ, United Kingdom.
- Arterioscler. Thromb. Vasc. Biol. 2007 Mar 1; 27 (3): 494-502.
ObjectiveThe regulation of endothelial cell adhesion molecules (CAMs) by vascular endothelial growth factor (VEGF) was investigated in cell cultures and in a rabbit model of atherogenic neointima formation.Methods And ResultsVEGF regulation of vascular CAM-1 (vascular cell adhesion molecule), intercellular CAM-1 (intercellular adhesion molecule), and E-selectin were investigated in human umbilical vein endothelial cells using quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and flow cytometry, and in the rabbit collar model of atherogenic macrophage accumulation by immunostaining. VEGF alone caused no significant induction of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, or E-selectin compared with tumor necrosis factor-alpha. In both hypercholesterolemic and normal rabbits, adenoviral VEGF-A165 expression caused no increase in endothelial vascular cell adhesion molecule-1 or E-selectin. In contrast, pretreatment of human umbilical vein endothelial cells with VEGF significantly increased E-selectin expression induced by tumor necrosis factor-alpha, compared with tumor necrosis factor-alpha alone, whereas vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 were unaffected. VEGF similarly enhanced IL-1beta-induced E-selectin upregulation. VEGF also synergistically increased tumor necrosis factor-alpha-induced E-selectin mRNA and shedding of soluble E-selectin. Synergistic upregulation of E-selectin expression by VEGF was mediated via VEGF receptor-2 and calcineurin signaling.ConclusionsVEGF alone does not activate endothelium to induce CAM expression; instead, VEGF "primes" endothelial cells, sensitizing them to cytokines leading to heightened selective pro-inflammatory responses, including upregulation of E-selectin.
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