Vascular endothelial growth factor (VEGF) is an endothelial cell (EC)-specific mitogen, and chemotactic agent, which is involved in wound repair, angiogenesis of ischemic tissue, tumor growth, microvascular permeability, vascular protection, and hemostasis. Over the past several years, there has been a major thrust towards developing therapies that either decrease VEGF levels or activity (e.g. Avastin in cancer), or increase VEGF (e.g. gene delivery strategies in ischemic heart disease). At the same time, there is increasing evidence that VEGF plays a role in modulating inflammation and coagulation. VEGF may alter EC phenotype through transcriptional and/or post-transcriptional mechanisms. Among the transcription factors that have been implicated in VEGF signaling are NF-kB, Egr-1, NF-AT, and GATA. The overall goal of this proposal is to identify the transcriptional mechanisms that underlie VEGF signaling in inflammation and coagulation.
The first aim will explore mechanisms by which VEGF induces expression of VCAM-1 and ICAM-1. In the second aim, siRNA and dominant negative approaches will be employed to map links between VEGF-responsive transcription factors and target gene expression/cellular function.
The third aim i s dedicated to an in vivo analysis of VEGF-responsive transcriptional networks in health and disease, with a particular emphasis on sepsis. A more complete understanding of the transcriptional mechanisms by which VEGF is coupled to endothelial cell phenotype should provide a framework for tailoring and fine tuning therapeutic modalities in vascular disease states. ? ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Goldman, Stephen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Beth Israel Deaconess Medical Center
United States
Zip Code
Tozawa, Hideto; Kanki, Yasuharu; Suehiro, Jun-ichi et al. (2011) Genome-wide approaches reveal functional interleukin-4-inducible STAT6 binding to the vascular cell adhesion molecule 1 promoter. Mol Cell Biol 31:2196-209
Suehiro, Jun-ichi; Hamakubo, Takao; Kodama, Tatsuhiko et al. (2010) Vascular endothelial growth factor activation of endothelial cells is mediated by early growth response-3. Blood 115:2520-32
Song, Haihua; Suehiro, Jun-ichi; Kanki, Yasuharu et al. (2009) Critical role for GATA3 in mediating Tie2 expression and function in large vessel endothelial cells. J Biol Chem 284:29109-24
Minami, Takashi; Yano, Kiichiro; Miura, Mai et al. (2009) The Down syndrome critical region gene 1 short variant promoters direct vascular bed-specific gene expression during inflammation in mice. J Clin Invest 119:2257-70
Choi, Eun Young; Chavakis, Emmanouil; Czabanka, Marcus A et al. (2008) Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment. Science 322:1101-4
Shapiro, Nathan I; Yano, Kiichiro; Okada, Hitomi et al. (2008) A prospective, observational study of soluble FLT-1 and vascular endothelial growth factor in sepsis. Shock 29:452-7
Yano, Kiichiro; Okada, Yoshiaki; Beldi, Guido et al. (2008) Elevated levels of placental growth factor represent an adaptive host response in sepsis. J Exp Med 205:2623-31
Abid, Md Ruhul; Spokes, Katherine C; Shih, Shou-Ching et al. (2007) NADPH oxidase activity selectively modulates vascular endothelial growth factor signaling pathways. J Biol Chem 282:35373-85