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• W2912777899 abstract "Abstract Aims- During embryogenesis, the onset of circulatory blood flow generates a variety of hemodynamic forces which reciprocally induce changes in cardiovascular development and performance. It has been known for some time that these forces can be detected by as yet unknown mechanosensory systems which in turn promote cardiogenic events such as outflow tract and aortic valve development. PIEZO1 is a mechanosensitive ion channel present in endothelial cells where it serves to detect hemodynamic forces making it an ideal candidate to play a role during cardiac development. We sought to determine whether PIEZO1 is required for outflow tract and aortic valve development. Methods and results- By analysing heart development in zebrafish we have determined that piezo1 is expressed in the developing outflow tract where it serves to detect hemodynamic forces. In particular, we have found that mechanical forces generated during the cardiac cycle activate Piezo1 which triggers nitric oxide to be released in the outflow tract. Consequently, disrupting Piezo1 signalling leads to defective outflow tract and aortic valve development and indicates this gene may be involved in the etiology of congenital heart diseases. Based on these findings, we analysed genomic data generated from a cohort of bicuspid aortic valve patients and identified 3 probands who each harboured a novel variant in PIEZO1 . Subsequent in vitro and in vivo assays indicates that these variants behave as dominant negatives leading to an inhibition of normal PIEZO1 mechanosensory activity and defective aortic valve development. Conclusion- These data indicate that the mechanosensitive ion channel piezo1 is required for OFT and aortic valve development and, furthermore, dominant negative variants of PIEZO1 appear to be associated with BAV in humans." @default.
• W2912777899 created "2019-02-21" @default.
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• W2912777899 date "2019-01-23" @default.
• W2912777899 modified "2023-10-17" @default.
• W2912777899 title "Piezo1 is required for outflow tract and aortic valve development" @default.
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• W2912777899 doi "https://doi.org/10.1101/528588" @default.
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