Formation of the arterial system is a complex series of steps that is, as yet, poorly understood. The process is largely driven by vascular endothelial growth factor (VEGF) and results in formation of new arteries during embryonic development and in adult tissues. In the previous funding cycle we have uncovered novel regulatory steps that appear to play central roles in regulation of arterial growth and branching. The current proposal is aimed at further our understanding of these events and beginning development of novel therapeutic strategies that can help millions of people with ischemic cardiovascular diseases. In particular, we propose to explore the role of a novel control point that affects two major signaling input to endothelial cells- the survival/vessel maintenance signal (Akt/eNOS) and the vessel growth signal (ERK). A detailed understanding of how this regulation is accomplished would go a long way to developing drugs that could [promote growth of new arteries. In addition, we propose to explore another novel aspect of VEGF signaling discovered by our lab- spatial control of VEGF receptor 2 (VEGFR2) signaling. These studies will explore where in the cell VEGFR2 signals, what controls its trafficking and how that process is regulated. Finally, with this knowledge in hand, we will explore how elevated cholesterol levels impair VEGF signaling and what steps can be taken to overcome that. Taken together, this is a comprehensive program aimed at further our understanding of a key biological process, arteriogenesis, that may result in development of new therapeutic approaches to treatment of coronary and peripheral;arterial diseases.

Public Health Relevance

The discovery of a signaling cascade controlling growth of new arteries will provide new insights and tools into developing new therapeutic strategies for treatment of atherosclerotic cardiovascular diseases including coronary, cerebral and peripheral vascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL084619-06
Application #
8105636
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Gao, Yunling
Project Start
2006-04-01
Project End
2015-05-31
Budget Start
2011-07-01
Budget End
2012-05-31
Support Year
6
Fiscal Year
2011
Total Cost
$610,915
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Yu, Pengchun; Wilhelm, Kerstin; Dubrac, Alexandre et al. (2017) FGF-dependent metabolic control of vascular development. Nature 545:224-228
Corti, Federico; Simons, Michael (2017) Modulation of VEGF receptor 2 signaling by protein phosphatases. Pharmacol Res 115:107-123
Chen, Pei-Yu; Simons, Michael (2016) When endothelial cells go rogue. EMBO Mol Med 8:1-2
Kofler, Natalie; Simons, Michael (2016) The expanding role of neuropilin: regulation of transforming growth factor-? and platelet-derived growth factor signaling in the vasculature. Curr Opin Hematol 23:260-7
Eelen, Guy; de Zeeuw, Pauline; Simons, Michael et al. (2015) Endothelial cell metabolism in normal and diseased vasculature. Circ Res 116:1231-44
Deng, Yong; Zhang, Xi; Simons, Michael (2015) Molecular controls of lymphatic VEGFR3 signaling. Arterioscler Thromb Vasc Biol 35:421-9
Cao, Zhongwei; Ding, Bi-Sen; Guo, Peipei et al. (2014) Angiocrine factors deployed by tumor vascular niche induce B cell lymphoma invasiveness and chemoresistance. Cancer Cell 25:350-65
Sakurai, Takashi; Woolls, Melissa J; Jin, Suk-Won et al. (2014) Inter-cellular exchange of cellular components via VE-cadherin-dependent trans-endocytosis. PLoS One 9:e90736
Yu, Pengchun; Tung, Joe K; Simons, Michael (2014) Lymphatic fate specification: an ERK-controlled transcriptional program. Microvasc Res 96:10-5
Morrison, Alan R; Yarovinsky, Timur O; Young, Bryan D et al. (2014) Chemokine-coupled ?2 integrin-induced macrophage Rac2-Myosin IIA interaction regulates VEGF-A mRNA stability and arteriogenesis. J Exp Med 211:1957-68

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