Abstract
Mitral valve prolapse (MVP) is a common form of valve disease and can lead to serious secondary complications. The recent identification of MVP causal mutations in primary cilia-related genes has prompted the investigation of cilia-mediated mechanisms of disease inception. Here, we investigate the role of platelet-derived growth factor receptor-alpha (PDGFRα), a receptor known to be present on the primary cilium, during valve development using genetically modified mice, biochemical assays, and high-resolution microscopy. While PDGFRα is expressed throughout the ciliated valve interstitium early in development, its expression becomes restricted on the valve endocardium by birth and through adulthood. Conditional ablation of Pdgfra with Nfatc1-enhancer Cre led to significantly enlarged and hypercellular anterior leaflets with disrupted endothelial adhesions, activated ERK1/2, and a dysregulated extracellular matrix. In vitro culture experiments confirmed a role in suppressing ERK1/2 activation while promoting AKT phosphorylation. These data suggest that PDGFRα functions to suppress mesenchymal transformation and disease phenotypes by stabilizing the valve endocardium through an AKT/ERK pathway.
Highlights
Mitral valve prolapse (MVP) is a common form of valve disease affecting 2–3% of the human population [1]
To characterize the expression profile of PDGFRα signaling during mitral valve development, we performed immunofluorescent staining on wildtype mouse mitral valve tissues from embryonic day 10.5 (E10.5) through adult time points
By postnatal day zero (P0), PDGFRα expression is mostly restricted to the membrane of endothelial cells lining the fibrosa region of both the anterior and posterior leaflets, a profile that is maintained through adulthood
Summary
Mitral valve prolapse (MVP) is a common form of valve disease affecting 2–3% of the human population [1]. Primary cilia are cellular antennae that protrude from the cell and as such, are able to respond to various extracellular signals including growth factors, extracellular matrix (ECM) components, and blood flow, among others. Recent reports have demonstrated that cilia mediated desert hedgehog signaling promotes the intercellular cytoskeletal organization of valve interstitial cells and proper valve morphogenesis [8]. Other signaling factors, including platelet derived growth factor (PDGF), have been implicated as functioning through the primary cilia in other contexts but studies of their function during valve morphogenesis has not yet been evaluated
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