Arteriogenesis is the process of formation of new arterial blood vessels during development or in the adult circulation. In development it entails formation of new endothelial vascular structures with arterial identity as defined by expression of key markers such ephrin B2 and neuropilin 1 followed by acquisition of the media and adventitia. In the adult circulation new arteries arise either by expansion of the pre-existing arterial vascular structures or de novo. Deletion of VEGF, its receptor VEGFR2 or key intracellular signaling mediators results in failure of arterial vasculature development. Defective arteriogenesis is noted in other setting including deletion of eNOS or in disease states such as diabetes and hypercholesterolemia and this failure contributes greatly to morbidity u and mortality associated with these diseases. Nevertheless, the entire process is little understood and there are no currently successful approaches to deal with its defects in clinical settings. Understanding of molecular mechanism regulating arteriogenesis would be of great benefit to our understanding of pathobiology of major cardiovascular illnesses and to development of new therapeutic approaches to combat them. In this PPG we propose a comprehensive approach to investigate the molecular basis of arteriogenesis and to develop new intellectual framework for therapeutic advances in this field. To this end, we will investigate a novel signaling pathway that seems to be critical to arteriogenesis (Project 1), study contributions of nitricoxide and the extracellular matrix (Project 2), evaluate the central role of mTOR in balancing various arteriogenic signaling inputs (Project 3) and determine the role of shear stress and other mechanical factors in initiating arteriogenesis in adult tissues (Project 4). The purpose of Core A is to coordinate programs of the entire PPG by providing scientific administration, scientific enhancement (speakers and seminars), and providing grant and program management.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL107205-02
Application #
8424229
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
2
Fiscal Year
2013
Total Cost
$76,238
Indirect Cost
$30,392
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kofler, Natalie; Simons, Michael (2016) The expanding role of neuropilin: regulation of transforming growth factor-β and platelet-derived growth factor signaling in the vasculature. Curr Opin Hematol 23:260-7
Sawyer, Andrew J; Kyriakides, Themis R (2016) Matricellular proteins in drug delivery: Therapeutic targets, active agents, and therapeutic localization. Adv Drug Deliv Rev 97:56-68
Baeyens, Nicolas; Bandyopadhyay, Chirosree; Coon, Brian G et al. (2016) Endothelial fluid shear stress sensing in vascular health and disease. J Clin Invest 126:821-8
Chen, Pei-Yu; Simons, Michael (2016) When endothelial cells go rogue. EMBO Mol Med 8:1-2
Kristofik, Nina; Calabro, Nicole E; Tian, Weiming et al. (2016) Impaired von Willebrand factor adhesion and platelet response in thrombospondin-2 knockout mice. Blood 128:1642-50
Baeyens, Nicolas; Larrivée, Bruno; Ola, Roxana et al. (2016) Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia. J Cell Biol 214:807-16
Siragusa, Mauro; Fröhlich, Florian; Park, Eon Joo et al. (2015) Stromal cell-derived factor 2 is critical for Hsp90-dependent eNOS activation. Sci Signal 8:ra81
Bancroft, Tara; Bouaouina, Mohamed; Roberts, Sophia et al. (2015) Up-regulation of thrombospondin-2 in Akt1-null mice contributes to compromised tissue repair due to abnormalities in fibroblast function. J Biol Chem 290:409-22
Eelen, Guy; de Zeeuw, Pauline; Simons, Michael et al. (2015) Endothelial cell metabolism in normal and diseased vasculature. Circ Res 116:1231-44
Simons, Michael; Eichmann, Anne (2015) Molecular controls of arterial morphogenesis. Circ Res 116:1712-24

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