Janice A. Nagy, PhD
Principal Associate in Pathology
Beth Israel Deaconess Medical Center
Harvard Medical School
330 Brookline Avenue, RN280F
Boston, MA 02215
Janice Nagy earned a Ph.D. in Biophysical Chemistry from Cornell University, Ithaca, NY in 1982. She then performed post-doctoral work at Harvard Medical School with Timothy A. Springer. In 1983 Dr. Nagy joined the Department of Pathology at Beth Israel Deaconess Medical Center as an Instructor and was promoted to Assistant Professor in 1990. In 1999 D. Nagy became a Principal Associate in Pathology and is currently a member of the CVBR.
VEGF and the Pathological Vascular Phenotype
The main focus of my research is to understand the role of a major tumor-secreted cytokine, Vascular Endothelial Growth Factor (VEGF-A), in the induction the pathological vascular phenotype. Whereas normal angiogenesis results in a well-ordered and highly functional vascular network, the pathological angiogenesis that is a conspicuous feature of tumor growth, ischemic diseases, and chronic inflammation, is characterized by vessels with aberrant angioarchitecture and compromised barrier function, and typically results from the unbalanced expression of VEGF-A.
Using an adenoviral vector strategy to overexpress VEGF-A in a variety of normal mouse tissues, we have identified six unique types of tumor surrogate blood vessels that closely resemble the blood vessels found in VEGF-A-expressing tumors. We have characterized the temporal, architectural and permeability properties of these vessels, and current studies are designed to investigate the molecular properties of these various vessel types to identify new targets for therapeutic intervention. Future studies will use our adenoviral approach to compare and contrast the distinctive characteristics of the VEGF-A-induced neovasculature with those elicited by other proangiogenic growth factors (e.g., FGF-2 and PlGF). Such an analysis will lead to a better understanding of pathological angiogenesis and will hopefully lead to new approaches to anti-angiogenic therapy.
In parallel studies, we made the unanticipated finding that VEGF-A can also induce a strong lymphangiogenic response. We found that the new "giant" lymphatics generated by VEGF-A overexpression were structurally and functionally abnormal: greatly enlarged with incompetent valves, sluggish flow, and delayed lymph clearance. They closely resembled the large lymphatics found in lymphangiomas and lymphatic malformations. These "giant" lymphatics, once formed, became VEGF-A independent and persisted indefinitely, long after VEGF-A expression ceased. These findings raise the possibility that similar, abnormal lymphatics develop in other pathologies in which VEGF-A is overexpressed, e.g., malignant tumors and chronic inflammation. Our current focus in this area is: 1) to gain insight into the specific VEGF/VEGF receptor signal transduction pathways responsible for this observed lymphatic vessel hyperplasia in vivo; and 2) to use laser capture microdissection and microarray analysis to further characterize the gene expression pattern of these "giant" lymphatics.
New and Noteworthy Publications
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Nagy JA, Benjamin L, Zeng H, Dvoral AM, Dvorak HF. Vascular permeability, vascular hyperpermeability and angiogenesis. (2008) Angiogenesis. 11:109-19.
This review provides a thorough discussion of the differences among basal, acute and chronic vascular permeability indicating that different microvessels are involved, different pathways of plasma extravasation are employed, the kinetics of vascular leakiness are different, the fluid extravasating has a different composition, and different control mechanisms likely regulate each type of permeability.
Nagy JA, Dvorak AM and Dvorak HF. VEGF-A and the Induction of Pathological Angiogenesis. (2007) Annual Reviews of Pathology 2:251-275.
This review summarizes the steps and mechanisms by which VEGF-A induces pathological angiogenesis, the properties of the resulting blood vessels, and the role of VEGF-A in human disease.
Nagy JA, Feng D, Vasile E, Wong WH, Shih SC, Dvorak AM, Dvorak HF. Permeability properties of tumor surrogate blood vessels induced by VEGF-A. (2006) Lab Invest. 86:767-80.
This study analyzes the permeability properties of the abnormal vessels generated by overexpression of VEGF-A and identifies which vessel types are permeable to plasma and plasma proteins that together account for the resulting edema characteristic of pathological angiogenesis.
Nagy JA and Senger DR. VEGF-A, cytoskeletal dynamics, and the pathological vascular phenotype. (2006) Exp Cell Res 312:535-548.
This review proposes that the serious structural and functional anomalies associated with VEGF-A-elicited neovessels reflect imbalances in the internal molecular cues that govern the directed assembly of endothelial cells into three-dimensional vascular networks and preserve barrier function thus drawing attention to role of endothelial cytoskeletal dynamics for proper neo-vascularization.
Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, Detmar MJ, Lawitts JA, Benjamin L, Tan X, Manseau EJ, Dvorak AM, Dvorak HF. Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. (2002) J. Exp Med. 196:1497-506.
This study was one of the first to demonstrate that overexpression of VEGF-A induces lymphangiogenesis that results in the formation of lymphatic vessels that are structurally and functionally abnormal.