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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL062289-15
Application #
8580391
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Gao, Yunling
Project Start
1999-05-01
Project End
2017-06-30
Budget Start
2013-07-23
Budget End
2014-06-30
Support Year
15
Fiscal Year
2013
Total Cost
$452,881
Indirect Cost
$177,035
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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
Moraes, Filipa; Paye, Julie; Mac Gabhann, Feilim et al. (2013) Endothelial cell-dependent regulation of arteriogenesis. Circ Res 113:1076-86
Ju, Rong; Simons, Michael (2013) Syndecan 4 regulation of PDK1-dependent Akt activation. Cell Signal 25:101-5
Corti, Federico; Finetti, Federica; Ziche, Marina et al. (2013) The syndecan-4/protein kinase Cýý pathway mediates prostaglandin E2-induced extracellular regulated kinase (ERK) activation in endothelial cells and angiogenesis in vivo. J Biol Chem 288:12712-21
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
Elfenbein, Arye; Simons, Michael (2013) Syndecan-4 signaling at a glance. J Cell Sci 126:3799-804
Elfenbein, Arye; Simons, Michael (2010) Auxiliary and autonomous proteoglycan signaling networks. Methods Enzymol 480:3-31
Elfenbein, Arye; Rhodes, John M; Meller, Julia et al. (2009) Suppression of RhoG activity is mediated by a syndecan 4-synectin-RhoGDI1 complex and is reversed by PKCalpha in a Rac1 activation pathway. J Cell Biol 186:75-83
Tirziu, Daniela; Simons, Michael (2009) Endothelium as master regulator of organ development and growth. Vascul Pharmacol 50:1-7
Partovian, Chohreh; Ju, Rong; Zhuang, Zhen W et al. (2008) Syndecan-4 regulates subcellular localization of mTOR Complex2 and Akt activation in a PKCalpha-dependent manner in endothelial cells. Mol Cell 32:140-9

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