ULTRASTRUCTURAL-LOCALIZATION OF VASCULAR-PERMEABILITY FACTOR VASCULARENDOTHELIAL GROWTH-FACTOR (VPF VEGF) TO THE ABLUMINAL PLASMA-MEMBRANEAND VESICULOVACUOLAR ORGANELLES OF TUMOR MICROVASCULAR ENDOTHELIUM/

Vascular permeability factor/vascular endothelial growth factor (VPF/V EGF) is a cytokine secreted by many animal and human tumors, activated macrophages, keratinocytes, rheumatoid synovial cells, embryonic tiss ues, and by cultured epithelial and mesenchymal cell lines. It acts se lectively on vascular endothelial cells to increase their permeability to circulating macromolecules and to stimulate their replication. Alt hough not detectably expressed by vascular cells in the human and anim al tumors we have studied, VPF/VEGF accumulates in the microvessels su pplying tumors and certain inflammatory reactions in which VPF/VEGF is also overexpressed. Light microscopic immunohistochemistry lacked the resolution necessary to localize VPF/VEGF precisely in such vessels, Therefore, we used a pre-embedding immunocytochemical method to locali ze VPF/VEGF at the ultrastructural level in the new blood vessels that are elicited in the peritoneal walls of mice bearing a transplantable mouse ascites tumor of ovarian origin, Intense immunostaining for VPE /VEGF was observed on the abluminal plasma membrane of tumor-associate d microvascular endothelial cells and in vesiculovacuolar organelles ( VVOs) present in these same endothelial cells. (VVOs are recently desc ribed cytoplasmic organelles present in tumor vascular endothelium tha t provide an important pathway for extravasation of circulating macrom olecules.) In contrast to labeling of the abluminal plasma membrane an d VVO vesicles and vacuoles, endothelial cytoplasmic organelles, such as multivesicular bodies and Weibel-Palade bodies, and the underlying basal lamina, did not stain with antibodies to VPF/VEGF. The distribut ion of VPF/VEGF here described corresponds to that anticipated for hig h-affinity VEP/VEGF receptors, although binding of VPF/VEGF to other e ndothelial cell surface structures, such as plasma membrane proteoglyc ans, is also a possibility.