The vasculature forms by a combination of vasculogenesis and angiogenesis. Convincing data indicate a role for vascular endothelial growth factor (VEGF) in both process. VEGF exists as three isoforms that arise by alternative splicing. Recent data suggest that the isoforms differ in their mitogenic potential but other functional differences have yet to be determined. In addition, the precise role and regulation of VEGF during vascular development are known. Finally, little is known about the molecules that maintain the adult vasculature in a differentiated, quiescent state. This proposal is founded on the hypothesis that specific molecules regulate vascular growth and differentiation. Our long-term objective is to identify these molecules and their functions. To accomplish this following aims are proposed. (1) To examine the expression and function of the VEGF isoforms during development in vivo. Isoform expression will be examined during mouse development using Rnase protection and in situ hybridization. Isoform function will be assessed by targeted exon deletion to generate mice expression specific VEGF isoforms. (2) To investigate the role and regulation of VEGF during vascular development. ES cells differentiated into embryoid bodies will be used as an in vitro model of vasculogenesis. The regulation of VEGF expression will be characterized in this model by studying the expression of stably transfected VEGF promoter/reporter constructs. VEGF isoform function will also be examined in this system. (3) To characterize the nature and function of a novel gene highly expressed by quiescent but not proliferating EC. This gene (frizzled) is homologous in C. elegans through humans. Expression studies in vivo and in vitro suggest the gene product may contribute to the regulation of endothelial growth and/or differentiation. Together the results of these investigations should add to our understanding of the mechanism (s) that regulate vascular growth and differentiation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA045548-11
Application #
6236923
Study Section
Project Start
1997-07-09
Project End
1998-03-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
11
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Adapala, R K; Thoppil, R J; Ghosh, K et al. (2016) Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy. Oncogene 35:314-22
Pelton, Kristine; Coticchia, Christine M; Curatolo, Adam S et al. (2014) Hypercholesterolemia induces angiogenesis and accelerates growth of breast tumors in vivo. Am J Pathol 184:2099-110
German, Alexandra E; Mammoto, Tadanori; Jiang, Elisabeth et al. (2014) Paxillin controls endothelial cell migration and tumor angiogenesis by altering neuropilin 2 expression. J Cell Sci 127:1672-83
Ingber, Donald E; Wang, Ning; Stamenovic, Dimitrije (2014) Tensegrity, cellular biophysics, and the mechanics of living systems. Rep Prog Phys 77:046603
Roy, R; Zurakowski, D; Wischhusen, J et al. (2014) Urinary TIMP-1 and MMP-2 levels detect the presence of pancreatic malignancies. Br J Cancer 111:1772-9
Procaccia, Vera; Nakayama, Hironao; Shimizu, Akio et al. (2014) Gleevec/imatinib, an ABL2 kinase inhibitor, protects tumor and endothelial cells from semaphorin-induced cytoskeleton collapse and loss of cell motility. Biochem Biophys Res Commun 448:134-8
Battinelli, Elisabeth M; Markens, Beth A; Kulenthirarajan, Rajesh A et al. (2014) Anticoagulation inhibits tumor cell-mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response. Blood 123:101-12
Li, Wenliang; Ai, Nanping; Wang, Suming et al. (2014) GRK3 is essential for metastatic cells and promotes prostate tumor progression. Proc Natl Acad Sci U S A 111:1521-6
Panigrahy, Dipak; Kalish, Brian T; Huang, Sui et al. (2013) Epoxyeicosanoids promote organ and tissue regeneration. Proc Natl Acad Sci U S A 110:13528-33
Minami, Takashi; Jiang, Shuying; Schadler, Keri et al. (2013) The calcineurin-NFAT-angiopoietin-2 signaling axis in lung endothelium is critical for the establishment of lung metastases. Cell Rep 4:709-23

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