Article
Lab Invest 2000, 80:99–115
Heterogeneity of the Angiogenic Response Induced in Different Normal Adult Tissues by Vascular Permeability Factor/Vascular Endothelial Growth Factor
This work was supported by United States Public Health Service National Institutes of Heath Grants CA-50453 (to HFD), AI-33372 (to RCM and AMD), and HL-59316, by funding from the Howard Hughes Medical Institute (to RCM) and by funding from the National Foundation for Cancer Research (to HFD). AP received fellowship support from the Wenner-Gren Foundation, Stockholm, Sweden.
Anna Pettersson2,3, Janice A Nagy1,3, Lawrence F Brown1, Christian Sundberg1, Ellen Morgan1, Steven Jungles2, Robert Carter2, Jose E Krieger2,4, Eleanor J Manseau1, V Susan Harvey1, Isabelle A Eckelhoefer1, Dian Feng1, Ann M Dvorak1, Richard C Mulligan2 and Harold F Dvorak1
- 1Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215
- 2Howard Hughes Medical Institute, Children's Hospital, and Harvard Institute of Human Genetics, Harvard Medical School, Boston, Massachusetts 02215
Correspondence: Dr. Harold F. Dvorak, Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02215. Fax: (617) 667-2943; E-mail: hdvorak@caregroup.harvard.edu
3The contributions of the first and second authors were equal.
4Present address for JEK: Heart Institute, University of Sao Paulo School of Medicine, Sao Paulo, Brazil.
Received 28 October 1999.
Abstract
Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is an angiogenic cytokine with potential for the treatment of tissue ischemia. To investigate the properties of the new blood vessels induced by VPF/VEGF, we injected an adenoviral vector engineered to express murine VPF/VEGF164 into several normal tissues of adult nude mice or rats. A dose-dependent angiogenic response was induced in all tissues studied but was more intense and persisted longer (months) in skin and fat than in heart or skeletal muscle (
3 weeks). The initial response (within 18 hours) was identical in all tissues studied and was characterized by microvascular hyperpermeability, edema, deposition of an extravascular fibrin gel, and the formation of enlarged, thin-walled pericyte-poor vessels ("mother" vessels). Mother vessels developed from preexisting microvessels after pericyte detachment and basement membrane degradation. Mother vessels were transient structures that evolved variably in different tissues into smaller daughter vessels, disorganized vessel tangles (glomeruloid bodies), and medium-sized muscular arteries and veins. Vascular structures closely resembling mother vessels and each mother vessel derivative have been observed in benign and malignant tumors, in other examples of pathological and physiological angiogenesis, and in vascular malformations. Together these data suggest that VPF/VEGF has a role in the pathogenesis of these entities. They also indicate that the angiogenic response induced by VPF/VEGF is heterogeneous and tissue specific. Finally, the muscular vessels that developed from mother vessels in skin and perimuscle fat have the structure of collaterals and could be useful clinically in the relief of tissue ischemia.
