Vascular permeability factor (VPF)-vascular endothelial growth factor (VEGF), has been proposed to be a mediator of endothelial proliferation and angiogenesis in normal and diseased states, and to have a role in the development of tumor-associated vascular hyperpermeability. The purpose of this study was to examine expression of the VPF-VEGF gene in both tumor and normal tissues. In a study of the levels of VPF-VEGF mRNA in 42 CNS neoplasms and 7 normal human brain samples, significantly higher levels (up to 10-fold higher) were observed in those tumors commonly associated with vascularity or cerebral edema (glioblastoma multiforme, hemangioblastoma, meningiomas). In those tumors not associated with increased vascularity and edema (pituitary adenomas and nonastrocytic gliomas), the levels of VPF-VEGF were not significantly different from those in normal brain. Cloning and sequencing of PCR-amplified GBM and normal brain cDNA demonstrated three forms of the VPF-VEGF coding region corresponding to mature polypeptides of 189, 165, and 121 amino acids, respectively. The relative abundance of the forms of VPF-VEGF mRNA was consistent in tumor and normal brain. Absorption of capillary permeability activity from human glioblastoma multiforme (GBM) cell conditioned medium and GBM cyst fluids by anti-VEGF antibodies demonstrated that VEGF is secreted by GBM cells and is present in sufficient quantities in vivo to induce vascular permeability. We used Northern blot analysis and in situ hybridization histochemistry to establish that VPF-VEGF mRNA is expressed in the brain, kidney, liver, lung, and spleen of the adult rat. On Northern blots, the relative abundance of VPF-VEGF mRNA observed in these tissues was highest in the lung and lowest in the spleen. As determined by in situ hybridization, the patterns of VPF-VEGF expression are organ-specific. Cloning studies in the rat demonstrate that multiple forms of VPF-VEGF are also expressed in the rat. The widespread expression and organ-specific distribution of VPF-VEGF mRNA in normal rat tissues, and the increased expression in human central nervous system tumors, suggest an extensive role for this factor in the physiology of both normal and tumor vasculature.
