Our extensive preliminary work has generated the unexpected hypothesis that the well-established apoptotic effect of transforming growth factor-beta 1 (TGF-bl) on endothelial cells is mediated by endogenous vascular endothelial growth factor (VEGF). This conclusion is based on our findings that TGF-bl stimulates endothelial cell expression of VEGF and that monoclonal antibodies to VEGF block TGF-bl-induced apoptosis. Because apoptosis is an essential component of vessel formation, this novel mechanism of endothelial cell apoptosis may have an important role in angiogenesis and vasculogenesis. We therefore propose: 1. To characterize the VEGF receptor(s) and downstream signaling pathways through which endogenous VEGF mediates the apoptotic activity of TGF-bl on endothelial cells. We will investigate signal transduction pathways activated by endogenous VEGF in response to TGF-bl treatment, and potential cross-talk between VEGF- and TGF-bl-specific pathways. The use of synthetic inhibitors and dominant negative mutants will afford to identify the signaling pathway(s) that mediate TGF-bl apoptotic signal(s). 2. To study the role of VEGF-mediated apoptosis in angiogenesis and vasculogenesis in vitro and in vivo. TGF-bl induces both apoptosis and vessel formation. Based on our preliminary work, we hypothesize that the angiogenic and vasculogenic activities of TGF-bl are mediated by VEGF with an autocrine mechanism. We propose to test our hypothesis using in vitro and vivo models of angiogenesis and vasculogenesis. The results will elucidate the mechanisms through which vessel formation is controlled by the interplay of VEGF and TGF-bl, two potent angiogenesis inducers. A detailed understanding of the mechanisms through which VEGF and TGF-bl interact can have important implications for the development of pharmacological treatments aimed to control angiogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL070203-04S1
Application #
7477457
Study Section
Pathology A Study Section (PTHA)
Program Officer
Goldman, Stephen
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2007
Total Cost
$63,064
Indirect Cost
Name
New York University
Department
Surgery
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Monti, Martina; Donnini, Sandra; Morbidelli, Lucia et al. (2013) PKC? activation promotes FGF-2 exocytosis and induces endothelial cell proliferation and sprouting. J Mol Cell Cardiol 63:107-17
Ferrari, Giovanni; Terushkin, Vitaly; Wolff, Martin J et al. (2012) TGF-?1 induces endothelial cell apoptosis by shifting VEGF activation of p38(MAPK) from the prosurvival p38? to proapoptotic p38?. Mol Cancer Res 10:605-14
Kallenbach, Klaus; Salcher, Rolf; Heim, Albert et al. (2009) Inhibition of smooth muscle cell migration and neointima formation in vein grafts by overexpression of matrix metalloproteinase-3. J Vasc Surg 49:750-8
Ferrari, Giovanni; Cook, Brandoch D; Terushkin, Vitaly et al. (2009) Transforming growth factor-beta 1 (TGF-beta1) induces angiogenesis through vascular endothelial growth factor (VEGF)-mediated apoptosis. J Cell Physiol 219:449-58
Yu, P-J; Ferrari, G; Pirelli, L et al. (2008) Thrombin cleaves the high molecular weight forms of basic fibroblast growth factor (FGF-2): a novel mechanism for the control of FGF-2 and thrombin activity. Oncogene 27:2594-601
Cook, Brandoch D; Ferrari, Giovanni; Pintucci, Giuseppe et al. (2008) TGF-beta1 induces rearrangement of FLK-1-VE-cadherin-beta-catenin complex at the adherens junction through VEGF-mediated signaling. J Cell Biochem 105:1367-73
D'Alessio, Silvia; Ferrari, Giovanni; Cinnante, Karma et al. (2008) Tissue inhibitor of metalloproteinases-2 binding to membrane-type 1 matrix metalloproteinase induces MAPK activation and cell growth by a non-proteolytic mechanism. J Biol Chem 283:87-99
Yu, Pey-Jen; Ferrari, Giovanni; Galloway, Aubrey C et al. (2007) Basic fibroblast growth factor (FGF-2): the high molecular weight forms come of age. J Cell Biochem 100:1100-8
Yu, Pey-Jen; Ferrari, Giovanni; Pirelli, Luigi et al. (2007) Vascular injury and modulation of MAPKs: a targeted approach to therapy of restenosis. Cell Signal 19:1359-71
Ferrari, Giovanni; Pintucci, Giuseppe; Seghezzi, Graziano et al. (2006) VEGF, a prosurvival factor, acts in concert with TGF-beta1 to induce endothelial cell apoptosis. Proc Natl Acad Sci U S A 103:17260-5

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