Harold F. Dvorak, MD
Professor of Pathology
Beth Israel Deaconess Medical Center
Department of Pathology
330 Brookline Avenue, RN-227C
Boston, MA 02215
Dvorak Lab >>
Residency training in Pathology at MGH; two years as a post-doc at NIH; 16 years as Staff Pathologist, MGH; 27 years as Chair of Pathology at BIH and then BIDMC; now doing full time research in vascular biology.
- Vascular Permeability
- Lymphangiogenesis (Vascular Permeability & Angiogenesis)
My major research interests are as follows:(1) Elucidate the mechanisms by which VEGF-secreting tumors induce the formation of new blood vessels and lymphatics. (2) Define the characteristics of these newly formed vessels. And (3) determine their response to anti-angiogenic therapy.
Tumors induce a heterogeneous neovascular response that includes angiogenesis, arteriogenesis, venogenesis and lymphangiogenesis; we have been able to mimic this response using an adenoviral vector expressing VEGF-A (Ad-VEGF-A164). Whether induced by tumors or by Ad-VEGF-A164, angiogenesis leads to the formation of at least four types of morphologically and functionally distinct blood vessels from preexisting venules: mother vessels (MV) form initially and subsequently differentiate into capillaries, glomeruloid microvascular proliferations (GMP) and vascular malformations (VM). Feeder arteries (FA), draining veins (DV) and giant lymphatics develop simultaneously from preexisting arteries, veins and lymphatics. Ad-VEGF-A164 offers the advantage that it induces the formation of each vessel type in large numbers, with predictable kinetics, and without the complicating presence of tumor cells. Particular interest focuses on determining the molecular properties of each vessel type, the molecular mechanisms by which each forms, and the identification of over-expressed molecules that could serve as therapeutic targets. Another closely related interest is to determine the structural and molecular mechanisms by which VEGF and other vascular permeability factors induce acute vascular permeability as well as the chronic vascular hyperpermeability that is characteristic of a subset of tumor microvessels, MV and GMP.
New and Noteworthy Publications
View all publications via PubMed >>
Zeng H, Qin L, Zhao D, Tan X, Manseau EJ, Van Hoang M, Senger DR, Brown LF, Nagy JA,
Dvorak HF. (2006) Orphan nuclear receptor TR3/Nur77 regulates VEGF-A-induced angiogenesis through its transcriptional activity. J Exp Med 203, p719.
This paper demonstrates that the angiogenic response induced by VEGF-A in vitro and in vivo is dependent on the expression and activation of the orphan nuclear receptor, TR3/Nur77; i.e., TR3/Nur77 is both necessary and sufficient for VEGF-A-induced angiogenesis.
Nagy JA, Feng D, Vasile E, Wong WH, Shih S-C, Dvorak AM,
Dvorak HF. (2006) Permeability properties of tumor surrogate blood vessels induced by VEGF-A. Lab Invest 86, p767.
This paper demonstrates that only a subset of angiogenic vessels induced by an adenovirus expressing VEGF-A (Ad-VEGF-A164), mother vessels and glomeruloid microvascular proliferations, is hyperpermeable to plasma proteins and presents a quantitative method for assessing both vascular permeability and the extent of the angiogenic response.
Nagy, JA, Dvorak AM, and
Dvorak HF. (2007) VEGF-A and the induction of pathological angiogenesis. Annu Rev Pathol Mech Dis 2, p251.
This paper reviews the steps and mechanisms by which VEGF-A induces angiogenesis and defines the six types of new blood vessels that comprise the angiogenic/arteriogenic/venogenic response.
Fu, Y, Nagy JA, Dvorak AM,
Dvorak HF. Tumor blood vessels: Structure and function (2007) in Antiangiogenesis agents, B. Teicher and L. Ellis, Editors. The Humana Press: Totowa, NJ. p205.
This paper documents that the six types of new blood vessels induced by Ad-VEGF-A164 are found in mouse and human tumors, validating the use of Ad-VEGF-A164 as a means of mimicking the tumor neovascular response. Thus, the six types of new blood vessels induced by Ad-VEGF-A164 are true tumor vessel surrogates.
Nagy, JA., Benjamin L, Zeng H, Dvorak AM,
Dvorak HF. (2008) Basal vascular permeability, acute vascular hyperpermeability and the chronic vascular hyperpermeability of pathological angiogenesis. Angiogenesis, in press.
This paper addresses the conflicting views held by physiologists and vascular biologists with regard to vascular permeability and reviews the methodology for quantifying permeability. Also, it demonstrates that vascular permeability must be considered under three headings (Basal Vascular Permeability, Acute Vascular Hyperpermeability, and Chronic Vascular Hyperpermeability) because each of these situations involves different microvessels, involves different pathways of fluid extravasation, and results in extravasates of different compositions.