While angiogenesis represents an important element of tissue response to ischemia or wounding and tumor-stimulated neovascularization plays a critical role in cancer's growth and expansion. At the same time relatively little new vessel growth takes place in most adult tissues including the myocardium. Although regulation of angiogenic response is an important part of normal and pathological homeostasis, little is known about the mechanisms of this control. One such control mechanism may involve the heparan sulfate matrix. Heparan sulfate proteoglycans (HSPG) can mediate both heparin- binding growth factor-receptor interaction at the cell surface as well as accumulation and storage of these growth factors in the extracellular matrix. Therefore any alteration of heparan sulfate composition on the cell surface or in the extracellular matrix can affect growth factor signaling. Recent observations have suggested that heparan sulfate chain carrying core proteins, in particular, syndecan-4, may play an important role in outside-in signaling by activating specific PKC isoenzymes and participating in PDZ domain-mediated assembly of intracellular protein complexes. In this grant application, we propose to explore these issues in the context of angiogenesis. In particular, we will study the effect of alterations in expression of heparan sulfate-carrying proteins in endothelial cells on functional properties of these cells in vitro and in vivo and investigate mechanisms responsible for these effects. It is hoped that better understanding of core protein/heparan sulfate chains control of endothelial cell function will provide new insights into the regulation of angiogenesis.
Chen, Pei-Yu; Simons, Michael (2016) When endothelial cells go rogue. EMBO Mol Med 8:1-2 |
Wang, Yingdi; Baeyens, Nicolas; Corti, Federico et al. (2016) Syndecan 4 controls lymphatic vasculature remodeling during mouse embryonic development. Development 143:4441-4451 |
Simons, Michael; Eichmann, Anne (2015) Molecular controls of arterial morphogenesis. Circ Res 116:1712-24 |
Baeyens, Nicolas; Mulligan-Kehoe, Mary Jo; Corti, Federico et al. (2014) Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling. Proc Natl Acad Sci U S A 111:17308-13 |
Ju, Rong; Zhuang, Zhen W; Zhang, Jiasheng et al. (2014) Angiopoietin-2 secretion by endothelial cell exosomes: regulation by the phosphatidylinositol 3-kinase (PI3K)/Akt/endothelial nitric oxide synthase (eNOS) and syndecan-4/syntenin pathways. J Biol Chem 289:510-9 |
Atri, Deepak; Larrivée, Bruno; Eichmann, Anne et al. (2013) Endothelial signaling and the molecular basis of arteriovenous malformation. Cell Mol Life Sci : |
Ju, Rong; Simons, Michael (2013) Syndecan 4 regulation of PDK1-dependent Akt activation. Cell Signal 25:101-5 |
Elfenbein, Arye; Simons, Michael (2013) Syndecan-4 signaling at a glance. J Cell Sci 126:3799-804 |
Lanahan, Anthony; Zhang, Xi; Fantin, Alessandro et al. (2013) The neuropilin 1 cytoplasmic domain is required for VEGF-A-dependent arteriogenesis. Dev Cell 25:156-68 |
Moraes, Filipa; Paye, Julie; Mac Gabhann, Feilim et al. (2013) Endothelial cell-dependent regulation of arteriogenesis. Circ Res 113:1076-86 |
Showing the most recent 10 out of 47 publications