NEOVASCULATURE INDUCED BY VASCULAR ENDOTHELIAL GROWTH-FACTOR IS FENESTRATED

We have reported previously that topical administration of vascular en dothelial growth factor(165) (VEGF) to a microvascular bed supplied wi th a continuous endothelium can rapidly induce the formation of endoth elial fenestrations (W. G. Roberts and G. E. Palade, J. Cell Sci., 108 : 2369-2379, 1995). From these results, we hypothesized that tumor vas culature, in general, may also be fenestrated because it has been repo rted that tumor secretion of VEGF causes the surrounding host vasculat ure to invade and feed the growing tumor. Using electron microscopy to characterize the endothelial cell morphology in tumor vessels from ei ther the periphery or the core of the tumor and immunoblotting to dete ct secreted VEGF, we analyzed the vasculature of human and murine neop lastic tumors grown s.c. in male nude mice. To clarify the role of VEG F(165) two models were used: (a) Chinese hamster ovary (CHO) cells sta bly transfected with hu VEGF(165) and injected into mice (VEGF:CHO tum ors); and (b) slow-release pellets containing purified VEGF or basic f ibroblast growth factor implanted on the rat cremaster muscle. All tum ors had vessels with fenestrated endothelium, open interendothelial ju nctions, and clustered fused caveolae. From all of the peripheral tumo r vessels observed, fenestrated endothelium was observed in 41% from E MT, 35% from M1S, 37% from U87, and 56% from VEGF:CHO tumors, whereas surrounding skin and muscle, from which tumor vessels were derived, ha d fenestrated endothelium in 2 and 0% of all vessels, respectively. Ad ditionally, further analysis revealed a substantial decrease in the an ionic glycocalyx on the luminal face of the fenestral diaphragms in en dothelium from tumors (especially VEGF:CHO) when compared to intestine or pancreas. Because the host tissue microvascular endothelium which supplies the tumor is not fenestrated, tumors can transform nonprolife rating, non-fenestrated vessels into proliferating vessels, many of wh ich have fenestrated endothelium. These data provide evidence that chr onic VEGF exposure can induce fenestrations in non-fenestrated endothe lium similar to the fenestrated endothelium found in tumor vessels.