Myxomatous valve disease (MVD) arises in 2-3% of the human population and causes mitral valve prolapse and regurgitation. Although rare inherited forms of MVD have been identified, most cases arise in previously healthy valves in older individuals. MVD is characterized by proliferation of valve interstitial cells (VICs), increased matrix production, and TGFb signaling, but how such changes arise in previously healthy valves is unknown. We have recently demonstrated that hemodynamic shear forces direct heart valve development through expression of the flow-regulated KLF2 and KLF4 transcription factors in valve endothelial cells (VECs), but whether and how the hemodynamic environment might regulate the function of the mature heart valve has not been addressed. Our preliminary studies reveal that inducible genetic loss of KLF2 and KLF4 in mature VECs results in a MVD phenotype associated with high VEC and VIC proliferation, increased matrix deposition, and evidence of pathologic endothelial- mesenchymal transition (EndMT). Importantly, we find that similar MVD pathology is conferred by loss of blood flow across the mitral valve of transplanted hearts. These findings support a novel mechanism for MVD in which changes in hemodynamic conditions that alter VEC KLF2/4 expression give rise to acquired MVD. This proposal will test this hemodynamic mechanism for MVD using new genetic tools to examine how blood flow and KLF2/4 in VECs control the cellular biology (Aim 1) and the matrix biology (Aim 2) of the mature valve. The proposed studies are expected to provide new insight into MVD pathogenesis, the role of blood flow in adult heart valve homeostasis, and the role of pathologic EndMT in the cardiovascular disease.
Myxomatous valve disease and associated mitral valve prolapse affects 2-3% of the population, but the molecular and cellular mechanisms that underlie it remain almost entirely unknown. Our preliminary studies reveal that blood flow and the KLF2 and KLF4 transcription factors activated by blood flow in valve endothelial cells are required to maintain healthy heart valves and prevent myxomatous valve pathology in mice. This proposal will examine the role of blood flow and KLF2 and KLF4 function in the healthy and myxomatous valve using mouse genetics and natural disease states in humans and dogs.
