VEGF INDUCES HYPERPERMEABILITY BY A DIRECT ACTION ON ENDOTHELIAL-CELLS

Vascular endothelial growth factor (VEGF) is a key regulator of vascul o- and angiogenesis. Earlier studies demonstrated a permeability-incre asing effect of VEGF in skin tests, leading to its other name, vascula r permeability factor. We wondered whether VEGF-induced hyperpermeabil ity was a direct effect of VEGF on endothelial cells and studied the p ermeability of human and porcine endothelial cell monolayers in a well -characterized in vitro system. VEGF increased the hydraulic conductiv ity up to 20-fold and simultaneously decreased the albumin reflection coefficient. This effect occurred after a delay of 150 min, although V EGF-induced early endothelial cell activation was verified by enhanced inositol phosphate accumulation within 5 min and increased P-selectin expression within 15 min. Platelet-derived growth factor and granuloc yte-macrophage colony-stimulating factor, two endothelial cell nonspec ific mitogens, also stimulated phosphatidylinositol metabolism and P-s electin expression; however, they had no effect; on endothelial permea bility. The increase in intracellular cyclic nucleotide levels of huma n endothelial monolayers abolished VEGF-induced endothelial hyperperme ability. In summary, VEGF increased endothelial permeability by a dire ct action on endothelial cells. Based on the pattern of endothelial ce ll activation by growth factors, VEGF appears to be a unique stimulus.