Angiogenesis plays a pivotal role in several important disease processes as well as in normal physiology. It is widely anticipated that modulation of angiogenesis (inhibition in tumors, stimulation in vascular insufficiency) will provide important therapeutic benefit. Many different cytokines and growth factors express angiogenic activity, of these VEGF-A stands out because of its potency, selectivity for vascular endothelium, and its consistent over expression in malignant tumors and in other clinical conditions in which angiogenesis plays an important role. VEGF-A acts selectively (though not exclusively) on endothelial cells (EC) by means of two high affinity receptor tyrosine kinases Flt-1(VEGFR-1) and KDR/Flk-1(VEGFR22) Both of these receptors are expressed at increased levels by BC during development and in pathophysiological angiogenesis. Since, most of the endothelial cells express both of the receptors and both of them can homodimerize upon binding to VEGF-A; therefore it is difficult to comprehend the molecular function of the individual receptor in the presence of the same ligand. The proposed study aims to dissect the functional aspects and sole responsiveness of these receptors for VEGF-A mediated signaling in EC. Chimeric receptors of both VEGFR-1 and -2 and their respective mutants will be utilized to study signaling pathways responsible for the individual receptors in vascular endothelial cells.
Aim 1 will focus to reveal the molecular function and dissect the signaling pathways for proliferation vs. migration channeling through VEGFR-2. We will also define the receptor(s) responsible for endothelial cell sprouting and its subsequent signaling pathways.
In Aim 2, investigation of the functional aspects of VEGFR-1 in endothelial cells will be performed. Furthermore, examination of inhibitory role of the VEGFR-1 for the VEGFR-2 function(s) and the pathways necessary for the inhibition will also be demonstrated. In addition, it will be tested whether VEGFR- 1 has any functional relationship with neuropilin-1, a new VEGF-A receptor of unknown function, particularly in EC migration.
In Aim 3, the data from Aims 1 and 2 will be utilized to evaluate the signaling pathways between normal vs. tumor-induced angiogenesis. A novel protein delivery system will be utilized or retroviral mediated genetic manipulation will be carried out to inactivate the target molecule(s) in normal as well as tumor-induced angiogenesis. By targeting the same signaling components in normal as well as tumor-induced angiogenesis, we will get a better picture and make a better comparison between these two events. The proposed study thus will delineate the individual role of the receptors in VEGF-A-mediated signaling and will also shed new light on the molecular mechanisms of angiogenesis. Taken together these experiments are likely to identify new therapeutic targets in order to combat angiogenesis in tumors and also in other disease processes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL070567-04
Application #
6868040
Study Section
Pathology A Study Section (PTHA)
Program Officer
Goldman, Stephen
Project Start
2002-04-01
Project End
2006-03-31
Budget Start
2004-04-03
Budget End
2005-03-31
Support Year
4
Fiscal Year
2004
Total Cost
$295,000
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Javeed, Naureen; Mukhopadhyay, Debabrata (2017) Exosomes and their role in the micro-/macro-environment: a comprehensive review. J Biomed Res 31:386-394
Wang, Ying; Cao, Ying; Mangalam, Ashutosh K et al. (2016) Neuropilin-1 modulates interferon-?-stimulated signaling in brain microvascular endothelial cells. J Cell Sci 129:3911-3921
Hoeppner, Luke H; Sinha, Sutapa; Wang, Ying et al. (2015) RhoC maintains vascular homeostasis by regulating VEGF-induced signaling in endothelial cells. J Cell Sci 128:3556-68
Hoeppner, Luke H; Wang, Ying; Sharma, Anil et al. (2015) Dopamine D2 receptor agonists inhibit lung cancer progression by reducing angiogenesis and tumor infiltrating myeloid derived suppressor cells. Mol Oncol 9:270-81
Wang, Ying; Cao, Ying; Yamada, Satsuki et al. (2015) Cardiomyopathy and Worsened Ischemic Heart Failure in SM22-? Cre-Mediated Neuropilin-1 Null Mice: Dysregulation of PGC1? and Mitochondrial Homeostasis. Arterioscler Thromb Vasc Biol 35:1401-12
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
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
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
Cao, Ying; Hoeppner, Luke H; Bach, Steven et al. (2013) Neuropilin-2 promotes extravasation and metastasis by interacting with endothelial ?5 integrin. Cancer Res 73:4579-4590
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

Showing the most recent 10 out of 73 publications