Angiogenesis is essential for tumor growth beyond minimal size and is important in many other pathophysiological situations. 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 VPF/VEGF stands out because of its potency, selectivity for vascular endothelium, and its consistent overexpression in malignant tumors and in other clinical conditions in which angiogenesis plays an important role. Very recently, we have described for the first time that the neurotransmitter dopamine (DA), which has long been used in the treatment of Parkinson's disease (as well as the treatment of cardiac failure), and DA D2 receptor agonists, potently and selectively blocks VPF/VEGF-induced angiogenesis in vivo, whether induced by tumors or by an adenoviral construct engineered to express VPF/VEGF. The experiments proposed here are designed to investigate the mechanistic details by which DA or its related compounds inhibit VPF/VEGF-induced angiogenesis.
In Aim 1, we will examine how DA D2 receptor, a G-protein coupled receptor (GPCR), can influence VEGFR-2 signaling pathways. By utilizing genetic and pharmacological approaches, Aim 2 will focus to reveal how peripheral DA might affect normal and pathological angiogenesis mediated by VPF/NEGF.
In Aim 3, investigation will be carried out to define the role of DA and its related molecules as anti-angiogenic agents in both tumor ascites as well as solid tumor models. Moreover, we will examine whether DA or related compounds can be employed with other conventional drugs (such as Taxol) in preclinical settings. Furthermore, the role of DA in angiogenesis mediated by other angiogenic molecules will also be investigated in animal models. Developmental angiogenesis in the retinas of newborn rats will be utilized to test the effect of DA in normal physiological angiogenesis. Taken together, the proposed studies will draw an important conceptual link between angiogenesis and the nervous system and suggest that DA, already in clinical use for other purposes, may have value in anti-angiogenesis therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072178-05
Application #
6979798
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Goldman, Stephen
Project Start
2002-12-05
Project End
2007-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
5
Fiscal Year
2006
Total Cost
$285,138
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Bhattacharya, Resham; Wang, Enfeng; Dutta, Shamit K et al. (2012) NHERF-2 maintains endothelial homeostasis. Blood 119:4798-806
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
Nandy, Debashis; Janardhanan, Rajiv; Mukhopadhyay, Debabrata et al. (2011) Effect of hyperglycemia on human monocyte activation. J Investig Med 59:661-7
Cao, Ying; Szabolcs, Annamaria; Dutta, Shamit K et al. (2010) Neuropilin-1 mediates divergent R-Smad signaling and the myofibroblast phenotype. J Biol Chem 285:31840-8
Nandy, Debashis; Mukhopadhyay, Debabrata; Basu, Ananda (2010) Both vascular endothelial growth factor and soluble Flt-1 are increased in type 2 diabetes but not in impaired fasting glucose. J Investig Med 58:804-6
Sinha, Sutapa; Cao, Ying; Dutta, Shamit et al. (2010) VEGF neutralizing antibody increases the therapeutic efficacy of vinorelbine for renal cell carcinoma. J Cell Mol Med 14:647-58
Verma, Anjali; Bhattacharya, Resham; Remadevi, Indu et al. (2010) Endothelial cell-specific chemotaxis receptor (ecscr) promotes angioblast migration during vasculogenesis and enhances VEGF receptor sensitivity. Blood 115:4614-22
Nandy, Debashis; Asmann, Yan W; Mukhopadhyay, Debabrata et al. (2010) Role of AKT-glycogen synthase kinase axis in monocyte activation in human beings with and without type 2 diabetes. J Cell Mol Med 14:1396-407
Muders, Michael H; Vohra, Pawan K; Dutta, Shamit K et al. (2009) Targeting GIPC/synectin in pancreatic cancer inhibits tumor growth. Clin Cancer Res 15:4095-103
Misra, Sanjay; Fu, Alex A; Puggioni, Alessandra et al. (2009) Proteomic profiling in early venous stenosis formation in a porcine model of hemodialysis graft. J Vasc Interv Radiol 20:241-51

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