Growth and branching of the arterial tree is a fundamental process underlying development, organ growth and recovery from a noxious insult. Despite its obvious biological importance, however, little is known about the molecular nature of these events and their regulation. We have recently discovered that synectin, a single domain PDZ protein, thought to be involved in the assembly of intracellular signaling complexes, play an important role in regulation of arteriogenesis and branching morphogenesis. Specifically, we have demonstrated that homozygous deletion of synectin gene in mice results in mice with under-developed arterial system with markedly reducing branching (""""""""the straight tube mouse"""""""") and impaired adult arteriogenesis. Remarkably, the defect is limited to the arterial and not the venous system. The availability of this mouse model provides us for the first time with the ability to devise an experimental program to gain new and fundamental insights into biology of arterial growth. In this grant, therefore, we propose to 1) Fully characterize the phenotype of synectin knockout mice focusing and arterial specificity of this defect 2) Establish which cell type is responsible for the abnormal arteriogenesis and branching morphogenesis and 3) Determine molecular events responsible for these events. Taken together, these three Aims will provide a comprehensive evaluation of the first known arteriogenic branching defect and will illuminate poorly explored and understood aspect of vascular biology. The proposal focuses on adult arteriogenesis because of its obvious practical significance. It is hoped that a better understanding of arterial growth in adult tissues will accelerate development of therapeutic angiogenesis strategies. ? ? ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVS-Q (03))
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Goldman, Stephen
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Dartmouth College
Internal Medicine/Medicine
Schools of Medicine
United States
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Chen, Dongying; Simons, Michael (2018) Reprogramming the Endocardium: Trials and Tribulations. Circ Res 122:913-915
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
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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
Simons, Michael; Eichmann, Anne (2015) Molecular controls of arterial morphogenesis. Circ Res 116:1712-24
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Deng, Yong; Zhang, Xi; Simons, Michael (2015) Molecular controls of lymphatic VEGFR3 signaling. Arterioscler Thromb Vasc Biol 35:421-9

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