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(American Journal of Pathology. 2001;158:1145-1160.)
© 2001 American Society for Investigative Pathology

Animal Models

Glomeruloid Microvascular Proliferation Follows Adenoviral Vascular Permeability Factor/Vascular Endothelial Growth Factor-164 Gene Delivery

Christian Sundberg, Janice A. Nagy, Lawrence F. Brown, Dian Feng, Isabelle A. Eckelhoefer, Eleanor J. Manseau, Ann M. Dvorak and Harold F. Dvorak

From the Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts

Glomeruloid bodies are a defining histological feature of glioblastoma multiforme and some other tumors and vascular malformations. Little is known about their pathogenesis. We injected a nonreplicating adenoviral vector engineered to express vascular permeability factor/vascular endothelial growth factor-164 (VPF/VEGF164) into the ears of athymic mice. This vector infected local cells that strongly expressed VPF/VEGF164 mRNA for 10 to 14 days, after which expression gradually declined. Locally expressed VPF/VEGF164 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, "mother" vessels. Glomeruloid body precursors were first detected at 3 days as focal accumulations of rapidly proliferating cells in the endothelial lining of mother vessels, immediately adjacent to cells expressing VPF/VEGF164. Initially, glomeruloid bodies were comprised of endothelial cells but subsequently pericytes and macrophages also participated. As they enlarged by endothelial cell and pericyte proliferation, glomeruloid bodies severely compromised mother vessel lumens and blood flow. Subsequently, as VPF/VEGF164 expression declined, glomeruloid bodies devolved throughout a period of weeks by apoptosis and reorganization into normal-appearing microvessels. These results provide the first animal model for inducing glomeruloid bodies and indicate that VPF/VEGF164 is sufficient for their induction and necessary for their maintenance.




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