Abstract
Heart valve disease is a major clinical problem worldwide. Cardiac valve development and homeostasis need to be precisely controlled. Hippo signaling is essential for organ development and tissue homeostasis, while its role in valve formation and morphology maintenance remains unknown. VGLL4 is a transcription cofactor in vertebrates and we found it was mainly expressed in valve interstitial cells at the post-EMT stage and was maintained till the adult stage. Tissue specific knockout of VGLL4 in different cell lineages revealed that only loss of VGLL4 in endothelial cell lineage led to valve malformation with expanded expression of YAP targets. We further semi-knockout YAP in VGLL4 ablated hearts, and found hyper proliferation of arterial valve interstitial cells was significantly constrained. These findings suggest that VGLL4 is important for valve development and manipulation of Hippo components would be a potential therapy for preventing the progression of congenital valve disease.
Highlights
Heart valves are critical for orchestrating the unidirectional blood flow during the cardiac cycle, ensuring the correct and efficient function of the heart [1]
VGLL4-eGFP reporter mouse line showed VGLL4 was mainly expressed in valve interstitial cells from post-endothelial-to-mesenchymal transition (EMT) stage to adult stage
We found that all organs, except heart, were smaller than Vgll4+/- and Vgll4+/+ controls, this is reflected by the ratio of heart weight to body weight which is significantly increased in Vgll4-/- mice (Fig 1E)
Summary
Heart valves are critical for orchestrating the unidirectional blood flow during the cardiac cycle, ensuring the correct and efficient function of the heart [1]. The valve primordia undergo extracellular matrix (ECM) remodeling and elongate into thin mature leaflets with three separate layers: the ventricularis (elastin-rich), fibrosa (fibrillar collagen-rich) and spongiosa (proteoglycan-rich). During this process, cell proliferation and apoptosis of VEC and VIC are precisely regulated, and, once disturbed, it will result in valve malformation [3, 4]. Valve disease can occur due to impaired cardiac cushion development, following infections or other elevated stress conditions such as heart attack, and usually lead to calcification or stenosis, eventually resulting in congestive heart failure [5]. The molecular mechanism underlying valve maturation and homeostasis remains incompletely understood so far
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