The lymphatic vasculature is essential for the maintenance of fluid balance in the body, for immune defense and for the uptake of dietary fat. Absent or damage lymphatic vessels lead to lymphedema, a chronic and disfiguring swelling of the extremities. In cancer patients the lymphatic vessels serve as a major route for the spread of tumor cells. Our long-term goal is to understand, at the molecular level, the mechanisms of lymphatic vessel growth, to identify the key molecules in the lymphatic endothelial differentiation program, and to use this knowledge to generate and differentiate lymphatic endothelial cells in vitro with a view to potential clinical applications, such as treatment of lymphedema. To address the regulation of the lymphatic endothelial differentiation program, transcription factors specifically expressed in the lymphatic endothelial cells (LECs), such as Prox-1 and eight other novel transcription factors identified in our preliminary studies, LECs or they will be overexpressed in blood vascular endothelial cells (BECs), and changes in the transcriptional programs of the two cell types will be monitored using DNA microarrays. To confirm our results in vivo, transgenic mice expressing inducible Prox-1 in blood vessels will be produced, and the expression of potential Prox-1 target genes will be studied. The transcriptional programs initiated in BECs and LECs upon stimulation with major regulators of angiogenesis and lymphangiogenesis, VEGF and VEGF-C, respectively, as well as with ligands specific for the three known VEGF receptors, will be studied. To understand the differences between lymphatic endothelial from different organs, human intestinal and skin LECs will be isolated, and molecules differentially expressed in the two cell populations will be identified. The tissue-specific expression of cell surface proteins in LECs from the skin and gut will be investigated using the in vivo/in vitro phage peptide and cDNA display approach. These studies will provide fundamental new insights into the mechanisms of lymphatic endothelial growth and differentiation. They should also identify molecular markers distinguishing superficial and visceral lymphatic vessels, which could then be used to develop targeted drug delivery to these vessels.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL075183-01
Application #
6708601
Study Section
Special Emphasis Panel (ZHL1-CSR-N (S1))
Program Officer
Goldman, Stephen
Project Start
2003-09-30
Project End
2007-08-31
Budget Start
2003-09-30
Budget End
2004-08-31
Support Year
1
Fiscal Year
2003
Total Cost
$250,000
Indirect Cost
Name
University of Helsinki
Department
Type
DUNS #
368904988
City
Helsinki
State
Country
Finland
Zip Code
00014
Tammela, Tuomas; Saaristo, Anne; Holopainen, Tanja et al. (2011) Photodynamic ablation of lymphatic vessels and intralymphatic cancer cells prevents metastasis. Sci Transl Med 3:69ra11
Anisimov, Andrey; Alitalo, Annamari; Korpisalo, Petra et al. (2009) Activated forms of VEGF-C and VEGF-D provide improved vascular function in skeletal muscle. Circ Res 104:1302-12
Karpanen, Terhi; Alitalo, Kari (2008) Molecular biology and pathology of lymphangiogenesis. Annu Rev Pathol 3:367-97
Karpanen, Terhi; Bry, Maija; Ollila, Hanna M et al. (2008) Overexpression of vascular endothelial growth factor-B in mouse heart alters cardiac lipid metabolism and induces myocardial hypertrophy. Circ Res 103:1018-26
Tammela, Tuomas; Zarkada, Georgia; Wallgard, Elisabet et al. (2008) Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454:656-60
Haiko, Paula; Makinen, Taija; Keskitalo, Salla et al. (2008) Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos. Mol Cell Biol 28:4843-50
Saharinen, Pipsa; Eklund, Lauri; Miettinen, Juho et al. (2008) Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts. Nat Cell Biol 10:527-37
Makinen, Taija; Alitalo, Kari (2007) Lymphangiogenesis in development and disease. Novartis Found Symp 283:87-98;discussion 98-105, 238-41
Tammela, Tuomas; Saaristo, Anne; Holopainen, Tanja et al. (2007) Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation. Nat Med 13:1458-66
Wirzenius, Maria; Tammela, Tuomas; Uutela, Marko et al. (2007) Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting. J Exp Med 204:1431-40

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