Pham, Duc2021-03-122022-08-272020-08Pham_cornellgrad_0058F_12218http://dissertations.umi.com/cornellgrad:12218https://hdl.handle.net/1813/103081246 pagesCongenital malformations of semilunar valves are common birth defects and often result in aortic valve stenosis and calcification with significant morbidity and mortality. The quest for new therapeutic targets remains a challenge in part because genetics alone does not fully address the etiology of congenital valve defects (CVDs). While altered blood flow in chick can lead to various CVDs that resemble those observed in humans, how hemodynamics drive valve development is still unclear. Here, we hypothesized that endocardial cells transduce mechanical information into biological programs that regulate semilunar valve morphogenesis. We utilized conditional loss-of-function mouse models and a primary valve endocardial cell 3D culture system to address two hallmarks of valve remodeling: extension and compaction. We revealed that low oscillatory shear stress is transduced by the endocardial cells on the inflow surface of the valve into bone morphogenetic protein (BMP) signaling programs that in turn regulate endocardial proliferation. In contrast, high fluid shear stress inhibits BMP signaling in endocardial cells, thereby restricting growth on the outflow surface. These findings have identified a novel mechanism for valve extension, in which differential endocardial growth constrains and drives valve growth and elongation in the direction of blood flow. In regard to mechanisms of valve compaction, we found that endocardial cells on the outflow side of the valve transduce high, unidirectional shear stress into endocardial Notch1 signaling that regulates CXCR4 expression in subendocardial cells. By regulating BMP and WNT signaling, CXCR4 modulates mesenchymal proliferation and induces matrix maturation and tissue compaction. These findings have uncovered a novel mechanobiological valve development program mediated by CXCR4 that has implications in the development of CVDs. This dissertation work has not only shed light on the interaction between blood flow and valve development programs but also the reactivation of developmental programs in adult valve disease initiation and progression. We provided prima facie evidence showing that aortic valve development and disease share side-specific BMP activation and CXCR4 signaling. Therefore, we hope this work will motivate further investigation of valve development mechanisms to inform better therapeutic and engineering strategies, not just for CVDs but also aortic valve disease.enAttribution 4.0 Internationaldevelopmentmechanobiologyoutflow tractsemilunarvalvedissertation or thesishttps://doi.org/10.7298/c0vm-wf20