investigations designed to identify the tumor-secreted factor responsible for the increased vascular permeability characteristic of nearly all malignant solid and ascites tumors. 3, 4, 12–18 VEGF is one of the most potent vascular permeability factors known, rendering vessels hyperpermeable to circulating macromolecules at subnanomolar concentrations and with a potency some 50 000 times that of histamine. 3, 4, 12–15, 18, 19 The onset of the vascular permeabilizing activity of VEGF is rapid, becoming evident within several minutes of injection. On the basis of this activity, it was first named vascular permeability factor.

It was only after these discoveries relating to vascular permeability that VEGF was also found to induce proliferation and migration of endothelial cells17, 20–23 and to stimulate endothelial cell expression of matrix-degrading proteases, including plasminogen activators and collagenases. 24, 25 Each of these activities undoubtedly contributes to the potent in vivo angiogenesis effects of VEGF, which were later