CHARACTERIZATION OF THE INCREASE IN VASCULAR-PERMEABILITY INDUCED BY VASCULAR-PERMEABILITY FACTOR INVIVO

1 Vascular permeability factor (VPF) is a protein secreted from a variety of human and rodent tumour and normal tissue cells. In addition to mediating angiogenesis and endothelial cell growth, VPF has been reported to be a potent mediator of increased microvascular permeability in vivo. In this study we have investigated these permeability changes in vivo using a quantitative model of local plasma leakage in rabbit skin. 2 Our results reveal that VPF is a potent mediator of plasma leakage which, in the rabbit, depends on a synergistic interaction with arteriolar vasodilators such as prostaglandin E2. The requirement for an exogenous vasodilator further suggests that VPF does not act to increase blood flow in this model. 3 We show that this response does not require the presence of circulating neutrophils and in this respect is similar to direct-action permeability increasing mediators such as histamine and bradykinin. Similarly, the time course of plasma leakage induced by VPF resembles that of direct-action mediators, where the greatest response occurs over the first 30 min. In contrast, the neutrophil-dependent plasma leakage induced by the active component of zymosan-activated plasma, C5a(des arg), was maintained at a similar level over 2.5 h. 4 Further, using mediator antagonists and enzyme inhibitors we demonstrate that the mechanism of action of VPF is not via activation of histamine, kinin, or platelet-activating factor pathways. Vascular permeability factor; permeability; vascular endothelial growth factor