The development and formation of normal and abnormal vasculature is of critical importance to both normal biology and disease pathogenesis. Recent studies from our and other laboratories have demonstrated the importance of syndecans in regulation of heparan-binding growth factors signaling on endothelial cells. Yet, despite the impressive degree of syndecan- dependent regulation of VEGF signaling, there is a very limited understanding of how this is accomplished. In preliminary studies, we have observed abnormal developmental angiogenesis in mice missing syndecan-2 and abnormal lymphatic morphogenesis in mice missing syndecan- 4. Furthermore, signaling studies point to VEGFA specificity for syndecan-2 and VEGFC specificity for syndecan-4. We propose to determine relative contributions of Syndecan-2 and Syndecan-4 to, respectively, VEGFR2-driven angiogenesis and VEGFR3-driven lymphangiogenesis both in development and in adult settings. The understanding of accounts for these signaling specificities would open-up the possibility of selectively targeting angiogenesis vs. lymphangiogenesis in a number of settings and, be, potentially, of tremendous clinical significance.

Public Health Relevance

We are focusing on the role of specific signaling cascades in endothelial cells that regulates some of the most fundamental properties of vascular development. A better understanding of this system will open new therapeutic possibilities for treating diseases such as heart attacks, stroke and peripheral vascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062289-20
Application #
9615010
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gao, Yunling
Project Start
1999-05-01
Project End
2021-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
20
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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
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
Corti, Federico; Finetti, Federica; Ziche, Marina et al. (2013) The syndecan-4/protein kinase C? pathway mediates prostaglandin E2-induced extracellular regulated kinase (ERK) activation in endothelial cells and angiogenesis in vivo. J Biol Chem 288:12712-21
Atri, Deepak; Larrivée, Bruno; Eichmann, Anne et al. (2013) Endothelial signaling and the molecular basis of arteriovenous malformation. Cell Mol Life Sci :

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