Dr. Dvorak's research is concerned with the steps and mechanisms of pathological angiogenesis and lymphangiogenesis as these occur in tumors, wound healing and inflammation. Of particular interest are the processes by which members of the VPF/VEGF family induce new blood and lymphatic vessels; the structural, functional and organizational characteristics of the various types of aberrant vessels that form; the relationship of each aberrant vessel type to the various types of new vessels found in pathological angiogenesis; and the differences between each of these vessel types and corresponding normal vessels.
The VPF/VEGF family includes VEGF-A and its several isoforms (189, 165 and 121 amino acid variants); VEGF-B; VEGF-C; VEGF-D; and PlGF. To study angiogenesis and lymphangiogenesis, we engineered adenoviral vectors that express these cytokines. These are then injected into various tissues of normal, immunodeficient mice where they induce an angiogenic response. Current work is evaluating the gene expression profile of each of the new blood vessel types (e.g., mother vessels, malformations, glomeruloid microvascular proliferations) and giant lymphatics induced by VEGF-A 164, other VEGF-A isoforms and PlGF with the goal of finding endothelial target molecules useful in anti-vascular cancer therapy. A longer term goal is to generate normal blood vessels by combining VEGF-A with other growth factors and inhibitors.
Selected Recent Publications
Schacht, V., Ramirez, M. I., Hong, Y. K., Hirakawa, S., Feng, D., Harvey, N., Williams, M., Dvorak, A. M., Dvorak, H. F., Oliver, G., and Detmar, M. T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. Embo J, 22: 3546-3556, 2003.
Feng, D., Nagy, J. A., Pyne, K., Dvorak, H. F., and Dvorak, A. M. Ultrastructural localization of platelet endothelial cell adhesion molecule (PECAM-1, CD31) in vascular endothelium. J Histochem Cytochem, 52: 87-101, 2004.
Satchi-Fainaro, R., Mamluk, R., Wang, L., Short, S. M., Nagy, J. A., Feng, D., Dvorak, A. M., Dvorak, H. F., Puder, M., Mukhopadhyay, D., and Folkman, J. Inhibition of vessel permeability by TNP-470 and its polymer conjugate, caplostatin. Cancer Cell,7: 251-261, 2005.
Stiver, S. I., Tan, X., Brown, L. F., Hedley-Whyte, E. T., and Dvorak, H. F. VEGF-A angiogenesis induces a stable neovasculature in adult murine brain. J Neuropathol Exp Neurol, 63: 841-855, 2004.
Dvorak, H. F. and Rickles, F. R. Malignancy and Hemostasis. In: R. W. Colman, J. Hirsh, V. J. Marder, A. W. Clowes, and J. N. George (eds.), Hemostasis and Thrombosis, 4th edition, pp. in press. Philadelphia: Lippincott Williams & Wilkins, 2005.