We study how mechanical forces control cell polarity and heterogeneous collective cell migration that we believe is essential for coordinated valve remodeling by related cellular fields (e.g. neural crest, anterior heart field, and epicardium). We hypothesize this is achieved through the coordination of integrin and cadherin signaling. We further utilize our bioreactor technologies to assess the mechanobiological and biomechanical influences integrin/cadherin signaling in valve formation/remodeling events. Among the key downstream mediators of cellular interaction with their environment (e.g. migration, contraction, Figure 1) are small GTPases such as RhoA and Rac1. We further identify novel interacting partners at these sub-cellular interfaces and elucidate their role using molecular gain/loss of function assays. At the cellular scale, we identify endocardial and mesenchymal specific requirements of adhesive signaling to coordinate tissue remodeling ECM patterning in vitro and in vivo. We study these in vivo using both avian and mouse model systems, the former with the benefit of our unique mechanical perturbation techniques, and the latter using cell type specific Cre drivers. We further test how these mechanically regulated adhesive signaling programs orchestrate known valvulogenic signaling pathways, and identify novel regulators via unbiased high throughput nucleotide sequencing (e.g. mRNA, miRNA). We then determine whether these same signaling mechanisms and pathways are involved in postnatal valve homeostasis and if their disruption regulates myxomatous or calcific degeneration using our previously published approaches. With this multi-scale mechanistic insight, we then test whether rebalancing adhesive signaling (first genetically and then via small molecule or targeted nanoparticles) is sufficient to improve fetal morphogenetic outcomes and/or inhibit postnatal valve degeneration.