A Novel Role for Endocardium in Perinatal Valve Development: Lessons Learned from Tissue-Specific Gene Deletion of the Tie1 Receptor Tyrosine Kinase

The mechanisms regulating late-gestational and early postnatal semilunar valve remodeling and maturation are poorly understood. Tie1 is a receptor tyrosine kinase with broad expression in embryonic endothelium. During semilunar valve development, Tie1 expression becomes restricted to the turbulent, arterial surfaces of the valves in the perinatal period. Previous studies in our laboratory have demonstrated that Tie1 can regulate cellular responses to blood flow and shear stress. We hypothesized that Tie1 signaling would regulate the flow-dependent remodeling of the semilunar valves associated with the conversion from maternal/placental to independent neonatal circulation. To circumvent the embryonic lethality of the Tie1 null mutation, we developed a floxed Tie1 allele and crossed it with an line that mediates gene excision exclusively in the endocardial cushion endothelium. Excision of Tie1 resulted in aortic valve leaflets displaying hypertrophy with perturbed matrix deposition. The valves demonstrated insufficiency and stenosis by ultrasound, and atomic force microscopy documented decreased stiffness in the mutant aortic valve consistent with an increased glycosaminoglycan to collagen ratio. These data suggest that active endocardial to mesenchymal signaling, at least partially mediated by Tie1, is uniquely required for normal remodeling of the aortic but not pulmonary valve in the late gestation and postnatal animal.