The Role Of Tie1in Lymphatic Remodeling And Valve Development

The lymphatic vascular system consists of the blind-ended lymphatic capillaries andcollecting lymphatic vessels. It plays an essential role in the maintenance of tissue fluidbalance, absorption of fatty acids, and immune surveillance. Lymphatic remodeling andmaturation are important processes during the formation of a functional lymphatic network.The detailed cellular and molecular mechanisms of lymphatic remodeling and maturationare still poorly understood. Tie1is a transmembrane tyrosine kinase receptor, and itsexpression is restricted to the endothelial cells and some hematopoietic cells. It has beenshown that Tie1plays a role in the establishment of blood vascular integrity andendothelial cell survival. Although deletion of Tie1was previously reported to haveabnormal lymphangiogenesis during embryonic development, it is unclear how Tie1isinvolved in this possess and whether Tie1plays a role in valve development. In this studywe employed Tie1conditional knockout mouse model, with its intracellular tyrosine kinasedomain targeted (Tie1-ICDFlox/Flox), to study the role of Tie1in lymphatic remodeling andvalve development. Firstly, we found that nearly70%of the Tie1△ICD/△ICDembryos werealive at E18.5. Expression analysis by RT-PCR and western-blot revealed that Tie1△ICDexpression level decreased in Tie1mutants compared with that of wild type control.Interestingly, Tie1△I CD/△ICDembryos had less severe vascular phenotypes in comparisonwith Tie1complete knockout mice (Tie1-/-). It is possible that Tie1△ICDretains the functionof Tie1and that the lethality of Tie1ΔICD/ΔICDmice may result from the low expression levelof Tie1ICD. Immunofluorescence staining of embryonic mice skin revealed that lymphaticnetwork became disorganized and no lymphatic valves were detected. Postnatal deletion ofTie1led to the abnormal formation of lymphatic network and the number of lymphaticvalves in pre-collector lymphatics decreased significantly in Tie1mutants in comparisonwith that of control mice. Further analysis by micro-lymphangiography showed thatlymphatic network was defective. Preliminary data from ear hole experiment demonstratedthat Tie1deficiency had no obvious effect on skin wound healing. We conclude that Tie1plays important role in lymphatic remodeling and valvedevelopment. It also implies that Tie1tyrosine kinase may not be required for vasculardevelopment.