Vascular Permeability Factor/Vascular Endothelial Growth Factor and the Significance of Microvascular Hyperpermeability in Angiogenesis

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Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) was originally discovered in the late 1970s because of its capacity to increase the permeability of microvessels to plasma and plasma proteins (Dvorak et al. 1979a,b). Using plastic-embedded, light microscopic section and, subsequent, immunohistochemistry, we noted that transplantable tumors growing in guinea pigs and rodents exhibit substantial deposits of fibrin in their stroma. Fibrin results from the clotting of fibrinogen, a 340kDa plasma protein which, under normal circumstances, is retained almost quantitatively within the blood vasculature. For fibrin to be deposited outside of blood vessels in tumor stroma, it was necessary that two requirements be met; namely, (1) that microvessels be abnormally hyperpermeable to permit the escape of fibrinogen and other plasma proteins necessary for blood clotting and (2) that there be a mechanism in place for activating the clotting system. In fact, both requirements were found to be met in tumors. The microvessels supplying tumors were hyperpermeable to fibrinogen and other plasma proteins, and both tumor cells and host stromal cells were capable of initiating extravascular coagulation via the tissue-factor pathway. Encouraged by these findings, we initiated a search for a tumor product that could account for tumor-vessels hyperpermeability. A potent vascular permeabilizing protein was soon found in serum-free tumor culture supernatants (Dvorak et al. 1979a,b) and was subsequently purified to homogeneity and given the name vascular permeability factor (VPF) (Senger et al. 1983, 1986, 1987, 1990).