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 project we propose to focus on a newly discovered interaction between PI3K/Akt and ERK signaling pathways that appears to control arterial fate determination. Specifically we will 1) establish biological significance of Rafl SA-mediated decoupling of ERK and Akt signaling during development and in the normal vasculature; 2) Determine biological significance of Rafl SA-mediated decoupling of ERK and Akt signaling in impaired arteriogenesis settings and 3) dissect how endothelial dysfunction alters VEGFR2 signaling in hypercholesterolemic conditions and study whether ERK activation mitigates this defect. Taken together, this set of experiments will provide a comprehensive look at this critical arterial fate-determining signaling cascade.

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 Program Projects (P01)
Project #
5P01HL107205-04
Application #
8791332
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
2016-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
4
Fiscal Year
2015
Total Cost
$595,775
Indirect Cost
$237,953
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06510
Chen, Dongying; Simons, Michael (2018) Reprogramming the Endocardium: Trials and Tribulations. Circ Res 122:913-915
MacLauchlan, Susan C; Calabro, Nicole E; Huang, Yan et al. (2018) HIF-1? represses the expression of the angiogenesis inhibitor thrombospondin-2. Matrix Biol 65:45-58
Zhang, Feng; Zarkada, Georgia; Han, Jinah et al. (2018) Lacteal junction zippering protects against diet-induced obesity. Science 361:599-603
Yu, Pengchun; Wu, Guosheng; Lee, Heon-Woo et al. (2018) Endothelial Metabolic Control of Lymphangiogenesis. Bioessays 40:e1700245
Kofler, Natalie; Corti, Federico; Rivera-Molina, Felix et al. (2018) The Rab-effector protein RABEP2 regulates endosomal trafficking to mediate vascular endothelial growth factor receptor-2 (VEGFR2)-dependent signaling. J Biol Chem 293:4805-4817
Bellini, C; Kristofik, N J; Bersi, M R et al. (2017) A hidden structural vulnerability in the thrombospondin-2 deficient aorta increases the propensity to intramural delamination. J Mech Behav Biomed Mater 71:397-406
Dejana, Elisabetta; Hirschi, Karen K; Simons, Michael (2017) The molecular basis of endothelial cell plasticity. Nat Commun 8:14361
Conway, Daniel E; Coon, Brian G; Budatha, Madhusudhan et al. (2017) VE-Cadherin Phosphorylation Regulates Endothelial Fluid Shear Stress Responses through the Polarity Protein LGN. Curr Biol 27:2727
Conway, Daniel E; Coon, Brian G; Budatha, Madhusudhan et al. (2017) VE-Cadherin Phosphorylation Regulates Endothelial Fluid Shear Stress Responses through the Polarity Protein LGN. Curr Biol 27:2219-2225.e5
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

Showing the most recent 10 out of 54 publications