A Role for Tie1 in Late Gestational Semilunar Valve Development

Abstract

Evaluation of late events in cardiovascular development is precluded mid-gestational embryonic lethality associated with most traditional endothelial specific gene knockouts. Thus, it has not been possible to study late gestational events in cardiovascular development using traditional methods. This study utilizes a conditional Tie1 floxed allele in conjunction with the NFAT-c1 P2 Cre specific for the pro-valvular endocardium thus allowing us to bypass the requirement for Tie1 in the developing vasculature. We provide evidence that Tie1 plays a context dependant role in the developing valve. Unlike its role in the vasculature, Tie1 is not required for endothelial cell survival/quiescence in the valve leaflet, but rather as a environmental sensor which relays information from the environment to the valvular interstitial cells. Deletion of Tie1 in the developing valve endocardium leads to an expansion of aortic valve size, as well as perturbations in ECM production and stratification, which is likely due to a miscommunication between the endothelial cells of the valve and the underlying valvular interstitial cells. In addition to being larger in size, aortic valve leaflets lacking Tie1 expression are much more pliable than wild type valves leading to aortic insufficiency and demise in these animals. We are the first to show that Tie1 plays a definitive role in valve remodeling and that Tie1 expression is essential for proper ECM stratification within the leaflet.