PROX1 inhibits PDGF-B expression to prevent myxomatous degeneration of heart valves

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ABSTRACT Background Cardiac valve disease (CVD) is observed in 2.5% of the general population and 10% of the elderly people. Effective pharmacological treatments are currently not available, and patients with severe CVD require surgery. PROX1 and FOXC2 are transcription factors that are required for the development of lymphatic and venous valves. We found that PROX1 and FOXC2 are expressed in a subset of valvular endothelial cells (VECs) that are located on the downstream (fibrosa) side of cardiac valves. Whether PROX1 and FOXC2 regulate cardiac valve development and disease is not known. Methods We used histology, electron microscopy and echocardiography to investigate the structure and functioning of heart valves from Prox1 ΔVEC mice in which Prox1 was conditionally deleted from VECs. Isolated valve endothelial cells and valve interstitial cells were used to identify the molecular mechanisms in vitro , which were tested in vivo by RNAScope, additional mouse models and pharmacological approaches. The significance of our findings was tested by evaluation of human samples of mitral valve prolapse (MVP) and aortic valve insufficiency. Results Histological analysis revealed that the aortic and mitral valves of Prox1 ΔVEC mice become progressively thick and myxomatous. Echocardiography revealed that the aortic valves of Prox1 ΔVEC mice are stenotic. FOXC2 was downregulated and platelet-derived growth factor-B (PDGF-B) was upregulated in the VECs of Prox1 ΔVEC mice. Conditional knockdown of FOXC2 and conditional overexpression of PDGF-B in VECs recapitulated the phenotype of Prox1 ΔVEC mice. PDGF-B was also increased in mice lacking FOXC2 and in human MVP and insufficient aortic valve samples. Pharmacological inhibition of PDGF-B signaling with imatinib partially ameliorated the valve defects of Prox1 ΔVEC mice. Conclusion PROX1 antagonizes PDGF-B signaling partially via FOXC2 to maintain the extracellular matrix composition and prevent myxomatous degeneration of cardiac valves. Novelty and Significance What Is Known? The transcription factors PROX1 and FOXC2 are critical regulators of lymphatic and venous valve development. PROX1 and FOXC2 are expressed in the downstream valvular endothelial cells of heart valves. What Is New? Deletion of Prox1 from the valvular endothelial cells of mice results in enlarged and myxomatous aortic and mitral valves. Aortic valves of the mutant ( Prox1 ΔVEC ) mice were stenotic. FOXC2 is partially responsible for the phenotype of Prox1 ΔVEC mice. PROX1 and FOXC2 inhibit the expression of the cytokine PDGF-B in heart valves. Hyperactivation of PDGF-B signaling results in aortic and mitral valve thickening. Inhibition of PDGF-B signaling ameliorates aortic valve stenosis in Prox1 ΔVEC mice. PDGFB is overexpressed and PROX1 is downregulated in human mitral valve prolapse (MVP) samples. Our findings suggest that PROX1 is an inhibitor of myxomatous valve disease that afflicts ~10% of the elderly population. We have also identified PDGF-B as a potential target for treating myxomatous valve disease.

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