Abstract 329: The Role of TIE1 in Flow Mediated Lymphatic Vessel Remodeling and Valvulogenesis

Abstract

Recently, it has been shown that the mechanical stimulus of turbulent shear stress caused by onset of lymph flow is required for lymphatic remodeling, maturation, and lymphatic valve (LV) development. Homeostasis of the adult lymphatic vasculature also relies on flow-mediated signal transduction. However, the cellular machinery responsible for transducing mechanosensory signals required for lymphatic network formation and maintenance is unknown. Our laboratory has previously shown that TIE1 is at least partially responsible for mechanotransduction of turbulent flow required for initiation and maintenance of atherosclerotic plaque formation at the branch points of systemic vasculature in the adult animal. Moreover, TIE1 is expressed throughout lymphatic vasculature during mouse embryogenesis into adulthood, with enrichment in LVs. To circumvent the embryonic lethality caused by global Tie1 disruption, we conditionally deleted Tie1 using Nfatc1Cre. Nfatc1Cre drives recombination in lymphatic endothelial cells, with strong expression in the LVs. Nfatc1Cre:Tie1fl/fl mutants survive to birth but accumulate chyle in the peritoneal and pleural cavities by postnatal day 2. The lymphatic vessels in the mutants are dilated and tortuous, and do not undergo normal hierarchical remodeling. The constrictions that normally indicate intraluminal valve development are lacking in the mutant lymphatic vessels. Underlying these defects in the Nfatc1Cre:Tie1fl/fl mutants is loss of the normal molecular landscape associated with lymphatic patterning and valvulogenesis. Therefore, we hypothesize that Tie1 orchestrates the mechanotransduction necessary for intraluminal LV development and postnatal maintenance.