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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:494.)
© 2007 American Heart Association, Inc.

Vascular Biology

Vascular Endothelial Growth Factor Synergistically Enhances Induction of E-Selectin by Tumor Necrosis Factor-

Anita K. Stannard; Rohit Khurana; Ian M. Evans; Vassiliki Sofra; David I.R. Holmes; Ian Zachary

From BHF Laboratories, Department of Medicine, University College London, United Kingdom.

Correspondence to Ian Zachary, BHF Laboratories, Department of Medicine, The Rayne Building, University College London, 5 University Street, London WC1E 6JJ, United Kingdom. E-mail i.zachary{at}ucl.ac.uk

Objective— The 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 Results— VEGF 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-. 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-, compared with tumor necrosis factor- alone, whereas vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 were unaffected. VEGF similarly enhanced IL-1ß–induced E-selectin upregulation. VEGF also synergistically increased tumor necrosis factor-–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.

Conclusions— VEGF 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.

VEGF alone caused no significant induction of cell adhesion molecule expression in endothelial cells or during neointima formation in vivo. However, VEGF pretreatment enhanced E-selectin expression induced by TNF-. These results indicate that VEGF "primes" endothelial cells to enhance selective responses to proinflammatory cytokines

Key Words: cell adhesion molecules • endothelial cells • IL-1ß

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