The long-term objective of our proposal is to elucidate the signaling pathways by which vascular permeability factor/vascular endothelial growth factor (VPF/VEGF, VEGF-A) promotes blood vessel formation and influences microenvironment. VEGF-A participates in a variety of vascular processes including endothelial cell (EC) proliferation, migration, survival, and differentiation (arterial-venous cell fate specification) through its two tyrosine kinase receptors, VEGFR-1 and VEGFR-2 and non-tyrosine kinase receptors neuropilins (NRPs). During the last two cycles of our funding, we defined several diverse and complex pathways of VEGF-A. These pathways focused mainly on proliferation, migration, and survival. Although there is striking evidence for distinct functional roles of VEGF-A-mediated signaling through VEGF receptors (VEGFRs), it is still unclear how certain VEGF-mediated downstream signal transduction cascades selectively potentiate two important functions: promotes EC differentiation and creates EC hyperpermeability. To understand the unique signaling pathways of VEGF-A, we have proposed two aims.
Aim 1 will delineate the roles of VEGFR-2 and NRPs for EC differentiation. We will also define the signaling pathways of VEGF-mediated p53 regulation and its role in EC differentiation. Similarly, the key role of Protein Kinase D (PKD) in VEGF-mediated EC differentiation will be evaluated. Whereas, Aim 2 will define the molecular mechanism of VEGF-induced vascular permeability (VP) in real-time. Recently we have developed a heat-inducible VEGF-A transgenic zebrafish model to study VP in real-time. In this aim, we will evaluate the role of individual VEGFRs and the molecules downstream of the pathways that lead to three distinctly different settings: basal vascular permeability (BVP), acute vascular hyperpermeability (AVH), and chronic vascular hyperpermeability (CVH). The proposed studies will elucidate the signaling pathways by which the known as well as unknown molecules mediate the different types of vascular permeability. Hence, the results of the proposed studies will promote understanding of the molecular mechanisms and pathways of these two important functions of VEGF-A and will impact our knowledge of normal physiological processes such as wound healing as well as pathological conditions, including cancer, diabetic retinopathy, and ischemic conditions leading to heart disease and stroke. Lastly, the proposed studies will expand our understanding of VEGF-A signaling as it relates to other VEGF-responsive cell types including circulating progenitor cells, bone cells, and neuronal progenitors.

Public Health Relevance

Vascular Permeability Factor/Vascular Endothelial Growth Factor (VPF/VEGF, VEGF-A) is arguably the most important angiogenic cytokine expressed by tumors, and it is expected that blocking VEGF-A signaling will be effective in controlling tumor angiogenesis and therefore limiting, or even reversing, tumor growth. On the other hand, there are several diseases in which we need to promote balanced angiogenesis including cardiovascular diseases. The proposed studies will map the critical signaling pathways responsible for two important functions of VEGF-A, endothelial cell (EC) differentiation and EC leakiness, and in the process identify key molecules that mediate these pathways. Hence, the results of the proposed studies will help us create more specific targets for potential angiogenesis inhibitors or promoters and can improve future therapies in various diseases including tumors, cardiovascular disease, and others.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Pal, Krishnendu; Cao, Ying; Gaisina, Irina N et al. (2014) Inhibition of GSK-3 induces differentiation and impaired glucose metabolism in renal cancer. Mol Cancer Ther 13:285-96
Gong, Xun; Sharma, Anil K; Strano, Michael S et al. (2014) Selective assembly of DNA-conjugated single-walled carbon nanotubes from the vascular secretome. ACS Nano 8:9126-36
Ulissi, Zachary W; Sen, Fatih; Gong, Xun et al. (2014) Spatiotemporal intracellular nitric oxide signaling captured using internalized, near-infrared fluorescent carbon nanotube nanosensors. Nano Lett 14:4887-94
Sinha, Sutapa; Pal, Krishnendu; Elkhanany, Ahmed et al. (2013) Plumbagin inhibits tumorigenesis and angiogenesis of ovarian cancer cells in vivo. Int J Cancer 132:1201-12
Bhattacharya, Resham; Wang, Enfeng; Dutta, Shamit K et al. (2012) NHERF-2 maintains endothelial homeostasis. Blood 119:4798-806
Holroyd, Eric W; Delacroix, Sinny; Larsen, Katarina et al. (2012) Tissue factor pathway inhibitor blocks angiogenesis via its carboxyl terminus. Arterioscler Thromb Vasc Biol 32:704-11
Vohra, Pawan K; Hoeppner, Luke H; Sagar, Gunisha et al. (2012) Dopamine inhibits pulmonary edema through the VEGF-VEGFR2 axis in a murine model of acute lung injury. Am J Physiol Lung Cell Mol Physiol 302:L185-92
E, Guangqi; Cao, Ying; Bhattacharya, Santanu et al. (2012) Endogenous vascular endothelial growth factor-A (VEGF-A) maintains endothelial cell homeostasis by regulating VEGF receptor-2 transcription. J Biol Chem 287:3029-41
Bhattacharya, Santanu; Roxbury, Daniel; Gong, Xun et al. (2012) DNA conjugated SWCNTs enter endothelial cells via Rac1 mediated macropinocytosis. Nano Lett 12:1826-30
Zhao, Xi; Bose, Anamika; Komita, Hideo et al. (2012) Vaccines targeting tumor blood vessel antigens promote CD8(+) T cell-dependent tumor eradication or dormancy in HLA-A2 transgenic mice. J Immunol 188:1782-8

Showing the most recent 10 out of 61 publications