Glomeruloid microvascular proliferation follows adenoviral vascular permeability factor/vascular endothelial growth factor-164 gene delivery

Glomeruloid bodies are a defining histological feature of glioblastoma mult iforme and some other tumors and vascular malformations. Little is known ab out their pathogenesis. We injected a nonreplicating adenoviral vector engi neered to express vascular permeability factor/vascular endothelial growth factor-164 (VPF/VEGF(164)) into the ears of athymic mice. This vector infec ted local cells that strongly expressed VPF/VEGF(164) mRNA for 10 to 14 day s, after which expression gradually declined. Locally expressed VPF/VEGF(16 4) induced an early increase in microvascular permeability, leading within 24 hours to edema and deposition of extravascular fibrin; in addition, many pre-existing microvessels enlarged to form thin-walled, pericyte-poor, "mo ther" vessels. Glomeruloid body precursors were first detected at 3 days as focal accumulations of rapidly proliferating cells in the endothelial lini ng of mother vessels, immediately adjacent to cells expressing VPF/VEGF(164 ) Initially, glomeruloid bodies were comprised of endothelial cells but sub sequently pericytes and macrophages also participated. As they enlarged by endothelial cell and pericyte proliferation, glomeruloid bodies severely co mpromised mother vessel lumens and blood flow. Subsequently, as VPF/VEGF(16 4) expression declined, glomeruloid bodies devolved throughout a period of weeks by apoptosis and reorganization into normal-appearing microvessels. T hese results provide the first animal model for inducing glomeruloid bodies and indicate that VPF/VEGF(164) is sufficient for their induction and nece ssary for their maintenance.