This proposal addresses the role of adenosine receptors in regulation of new blood vessel growth. Our research suggests that adenosine receptors induce synthesis of angiogenic factors in hypoxic tissues and promote homing of endothelial progenitor cells to the ischemic heart. The goal of the current application is to study the role of adenosine A2B receptors in regulation of cell proliferation and modulation of pro-angiogenic properties of cardiac and bone marrow stem/progenitor cells. Due to their low affinity to adenosine, A2B receptors are likely to remain silent under physiological conditions, but are engaged during ischemic injury when extracellular adenosine levels are increased. Based on our preliminary observations in Sca1-positive cardiac stem cells, we hypothesize that activation of A2B receptors stimulates stem cell proliferation and increases VEGF production via beta-catenin/Tcf signaling axis of the canonical Wnt pathway. If our hypothesis is correct, this would imply that the A2B receptor may regulate paracrine functions and survival of therapeutically administered cells. We will test this hypothesis in Specific Aim 1 by examining the role of adenosine receptors and associated intracellular pathways in regulation of beta-catenin/Tcf signaling axis in isolated Sca1-positive cardiac stem cells.
In Specific Aim 2, we will evaluate the role of adenosine A2B receptors in Sca1-positive cardiac stem cell proliferation and VEGF production in vivo.
In Specific Aim 3, we will determine the role of this receptor subtype in survival and angiogenic properties of bone marrow stem/progenitor cells transplanted into the heart. Finally, in Specific Aim 4 we will determine the contribution of adenosine A2B receptors to the therapeutic effects of cardiac and bone marrow stem cells in an acute myocardial infarction model. Elucidation of the role of adenosine receptors in these cells will not only contribute to our understanding of molecular mechanisms of neovascularization, but may also result in improvement of cell-based therapies being developed to treat ischemic diseases.

Public Health Relevance

The use of adult stem cells holds great promise for treatment of cardiovascular disease. The goal of this proposal is to understand the role of specific cell surface molecules called adenosine receptors in new blood vessel growth induced by stem cells. This knowledge may improve cell-based therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095787-03
Application #
8197609
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Olive, Michelle
Project Start
2010-01-12
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
3
Fiscal Year
2012
Total Cost
$386,100
Indirect Cost
$138,600
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Ryzhov, Sergey; Sung, Bong Hwan; Zhang, Qinkun et al. (2014) Role of adenosine A2B receptor signaling in contribution of cardiac mesenchymal stem-like cells to myocardial scar formation. Purinergic Signal 10:477-86
Ryzhov, Sergey V; Pickup, Michael W; Chytil, Anna et al. (2014) Role of TGF-? signaling in generation of CD39+CD73+ myeloid cells in tumors. J Immunol 193:3155-64
Ryzhov, Sergey; Biktasova, Asel; Goldstein, Anna E et al. (2014) Role of JunB in adenosine A2B receptor-mediated vascular endothelial growth factor production. Mol Pharmacol 85:62-73
Ryzhov, Sergey; Zhang, Qinkun; Biaggioni, Italo et al. (2013) Adenosine A2B receptors on cardiac stem cell antigen (Sca)-1-positive stromal cells play a protective role in myocardial infarction. Am J Pathol 183:665-72
Ryzhov, Sergey; Goldstein, Anna E; Novitskiy, Sergey V et al. (2012) Role of A2B adenosine receptors in regulation of paracrine functions of stem cell antigen 1-positive cardiac stromal cells. J Pharmacol Exp Ther 341:764-74
Aisagbonhi, Omonigho; Rai, Meena; Ryzhov, Sergey et al. (2011) Experimental myocardial infarction triggers canonical Wnt signaling and endothelial-to-mesenchymal transition. Dis Model Mech 4:469-83
Ryzhov, Sergey; Novitskiy, Sergey V; Goldstein, Anna E et al. (2011) Adenosinergic regulation of the expansion and immunosuppressive activity of CD11b+Gr1+ cells. J Immunol 187:6120-9
Feoktistov, Igor; Biaggioni, Italo (2011) Role of adenosine A(2B) receptors in inflammation. Adv Pharmacol 61:115-44