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.
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.
|Kofler, Natalie; Simons, Michael (2016) The expanding role of neuropilin: regulation of transforming growth factor-Î² and platelet-derived growth factor signaling in the vasculature. Curr Opin Hematol 23:260-7|
|Chen, Pei-Yu; Simons, Michael (2016) When endothelial cells go rogue. EMBO Mol Med 8:1-2|
|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|
|Faber, James E; Chilian, William M; Deindl, Elisabeth et al. (2014) A brief etymology of the collateral circulation. Arterioscler Thromb Vasc Biol 34:1854-9|
|Zhang, Xi; Simons, Michael (2014) Receptor tyrosine kinases endocytosis in endothelium: biology and signaling. Arterioscler Thromb Vasc Biol 34:1831-7|
|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|
|Ricard, Nicolas; Simons, Michael (2014) Fox(y) regulators of VEGF receptors. Circ Res 115:683-5|
|Morrison, Alan R; Yarovinsky, Timur O; Young, Bryan D et al. (2014) Chemokine-coupled Î²2 integrin-induced macrophage Rac2-Myosin IIA interaction regulates VEGF-A mRNA stability and arteriogenesis. J Exp Med 211:1957-68|
|Chen, Pei-Yu; Qin, Lingfeng; Zhuang, Zhen W et al. (2014) The docking protein FRS2Î± is a critical regulator of VEGF receptors signaling. Proc Natl Acad Sci U S A 111:5514-9|
Showing the most recent 10 out of 37 publications