Abnormal lymphangiogenesis leading to lymphedema is a common disorder afflicting tens of millions of individuals throughout the world. Yet, despite its frequency, its etiology is poorly understood and no effective therapies are available. In the present study we are focusing on the role of syndecan-2 and syndecan-4 in formation of lymphatic vasculature during development and in adult life. In preliminary studies we have demonstrated that both syndecans play a role in polarization of the lymphatic endothelium and formation of lymphatic valves. The absence of either syndecan results in formation of giant lymphatics with multiple excessive valves. These results suggest that these two syndecans are central to lymphatic development and lymphatic valve morphogenesis. We propose, therefore, to 1) define molecular mechanisms of syndecan- 2 signaling;2) define lymphatic vasculature and lymphatic valve morphogenesis defects in syndecan-2 and 4 knockout mice and 3) investigate how syndecans 2 and 4 sense shear stress and use that ability to regulate valve formation. Taken together these studies for the first time will paint a comprehensive picture of molecular signaling events and linked physical forces that underlie formation of the lymphatic system.
We have identified two genes, syndecan-2 and syndecan-4, that control how cells lining blood and lymphatic vessels align inside them. The importance of this process is that it controls the size and maturity of these vessels and is involved in a range f common cardiovascular illnesses.
|Chen, Pei-Yu; Simons, Michael (2016) When endothelial cells go rogue. EMBO Mol Med 8:1-2|
|Simons, Michael; Eichmann, Anne (2015) Molecular controls of arterial morphogenesis. Circ Res 116:1712-24|
|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|
|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|
|Corti, Federico; Finetti, Federica; Ziche, Marina et al. (2013) The syndecan-4/protein kinase CÎ± pathway mediates prostaglandin E2-induced extracellular regulated kinase (ERK) activation in endothelial cells and angiogenesis in vivo. J Biol Chem 288:12712-21|
|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|
|Atri, Deepak; LarrivÃ©e, Bruno; Eichmann, Anne et al. (2013) Endothelial signaling and the molecular basis of arteriovenous malformation. Cell Mol Life Sci :|
|Moraes, Filipa; Paye, Julie; Mac Gabhann, Feilim et al. (2013) Endothelial cell-dependent regulation of arteriogenesis. Circ Res 113:1076-86|
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