Project Summary Myxomatous valve disease (MVD) is among the most common types of cardiac valve disease and carries significant morbidity and mortality, leading to regurgitation and valve prolapse. While most of the research efforts at understanding MVD pathogenesis have focused on mouse models of syndromic MVD, the majority of MVD patients lack known syndromic mutations and present later in life, suggesting that MVD is more often acquired and likely influenced by environmental factors. We have recently demonstrated that hemodynamic shear forces direct cardiac valve development through transcription factors KLF2 and KLF4, but the role of hemodynamic forces and KLF2/4 in regulating mature valve homeostasis remains unexplored. Preliminary studies indicate that genetic inducible loss of KLF2/4 from valve endothelial cells (VEC) results in a phenotype highly concordant with human MVD. Importantly, similar MVD pathology results from transplanted hearts with loss of blood flow across the mitral valve. Together, these results suggest a role for hemodynamic forces and KLF2/4 as critical regulators of valve homeostasis. This proposal aims to characterize the role of hemodynamic forces in maintaining valve homeostasis (Aim 1), identify specific targets of VEC KLF2/4 (Aim 2) and determine whether TGFß/Smad signaling is a shared requirement for myxomatous pathology in models of both syndromic and acquired MVD (Aim 3).