Molecular mechanisms of lymphangiogenesis: role of VEGFR-3 mediated signaling
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چکیده
......................................................................................................................................................................... 6 REVIEW OF THE LITERATURE................................................................................................................................... 7 1. CELL SIGNALING BY RECEPTOR TYROSINE KINASES..................................................................................................... 7 1.1. RTK activation ...................................................................................................................................................... 7 1.2. Signal transduction ............................................................................................................................................... 8 1.3. Signal down-regulation ........................................................................................................................................ 9 2. DEVELOPMENT OF THE VASCULAR SYSTEM................................................................................................................ 10 2.1. Vasculogenesis and angiogenesis ...................................................................................................................... 10 2.2. Lymphangiogenesis............................................................................................................................................. 11 2.3. Phylogeny of blood and lymphatic vessels......................................................................................................... 12 2.4. Molecular identity of lymphatic versus blood vascular endothelial cells ........................................................ 13 3. MOLECULAR REGULATION OF VASCULAR DEVELOPMENT ......................................................................................... 14 3.1. Angiogenic and lymphangiogenic factors.......................................................................................................... 14 3.1.1. VEGF family of growth factors ....................................................................................................................... 15 3.1.2. Angiopoietin family.......................................................................................................................................... 17 3.2. Endothelial cell receptors................................................................................................................................... 17 3.2.1. VEGF receptors ............................................................................................................................................... 17 3.2.2. Tie receptors .................................................................................................................................................... 19 3.2.3. Neuropilins....................................................................................................................................................... 19 3.3. VEGFs and VEGFRs in the development of other organ systems .................................................................... 20 4. PATHOLOGIC CONDITIONS INVOLVING BLOOD AND LYMPHATIC VESSELS ................................................................ 21 4.1. Tumor development and progression................................................................................................................. 21 4.2. Lymphedema ....................................................................................................................................................... 22 AIMS OF THE STUDY .................................................................................................................................................... 25 MATERIALS AND METHODS...................................................................................................................................... 26 RESULTS AND DISCUSSION........................................................................................................................................ 29 1. NEUROPILIN-1 IS A RECEPTOR FOR VEGF-B (I)......................................................................................................... 29 2. VEGFR-3 IS REQUIRED FOR THE DEVELOPMENT AND MAINTENANCE OF THE EMBRYONIC LYMPHATIC VASCULATURE (II) ........................................................................................................................................................... 30 3. VEGFR-3 TRANSDUCES LYMPHATIC ENDOTHELIAL CELL GROWTH, SURVIVAL AND MIGRATION SIGNALS (III)..... 32 3.1. Isolation of lymphatic endothelial cells ............................................................................................................. 33 3.2. VEGFR-3 signal transduction ............................................................................................................................ 33 4. A GENETIC PROGRAM CONTROLLING THE LYMPHATIC VERSUS BLOOD VASCULAR ENDOTHELIAL CELL PHENOTYPE (IV) .................................................................................................................................................................................. 34 4.1. Gene expression profiling of lymphatic and blood vascular endothelial cells................................................. 34 4.2. Adhesion molecules in lymphatic and blood vascular endothelial cells .......................................................... 35 4.3. Prox-1 as a fate determining factor for lymphatic endothelial cells ................................................................ 36 CONCLUDING REMARKS ............................................................................................................................................ 37 ACKNOWLEDGEMENTS .............................................................................................................................................. 38 REFERENCES ................................................................................................................................................................... 39
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