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Piezo1 is required for outflow tract and aortic valve development

Adèle Faucherre, Hamid Moha ou Maati, Nathalie Nasr, Amélie Pinard, Alexis Theron, Gaëlle Odelin, Jean-Pierre Desvignes, David Salgado, Gwenaëlle Collod-Béroud, Jean-François Avierinos, Guillaume Lebon, Stéphane Zaffran, Chris Jopling
doi: https://doi.org/10.1101/528588
Adèle Faucherre
1IGF, CNRS, INSERM, Univ. Montpellier, LabEx ICST, F-34094 Montpellier, France
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Hamid Moha ou Maati
1IGF, CNRS, INSERM, Univ. Montpellier, LabEx ICST, F-34094 Montpellier, France
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Nathalie Nasr
1IGF, CNRS, INSERM, Univ. Montpellier, LabEx ICST, F-34094 Montpellier, France
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Amélie Pinard
2Aix Marseille Univ, INSERM, MMG UMR1251, 13005 Marseille, France.
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Alexis Theron
2Aix Marseille Univ, INSERM, MMG UMR1251, 13005 Marseille, France.
3Service de Chirurgie Cardiaque, AP-HM, Hôpital de la Timone, 13005, Marseille, France.
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Gaëlle Odelin
2Aix Marseille Univ, INSERM, MMG UMR1251, 13005 Marseille, France.
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Jean-Pierre Desvignes
2Aix Marseille Univ, INSERM, MMG UMR1251, 13005 Marseille, France.
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David Salgado
2Aix Marseille Univ, INSERM, MMG UMR1251, 13005 Marseille, France.
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Gwenaëlle Collod-Béroud
2Aix Marseille Univ, INSERM, MMG UMR1251, 13005 Marseille, France.
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Jean-François Avierinos
2Aix Marseille Univ, INSERM, MMG UMR1251, 13005 Marseille, France.
4Service de Cardiologie, AP-HM, Hôpital de la Timone, 13005, Marseille, France.
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Guillaume Lebon
1IGF, CNRS, INSERM, Univ. Montpellier, LabEx ICST, F-34094 Montpellier, France
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Stéphane Zaffran
2Aix Marseille Univ, INSERM, MMG UMR1251, 13005 Marseille, France.
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Chris Jopling
1IGF, CNRS, INSERM, Univ. Montpellier, LabEx ICST, F-34094 Montpellier, France
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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.

Footnotes

  • ↵† Co-first authors.

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Posted January 23, 2019.
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Piezo1 is required for outflow tract and aortic valve development
Adèle Faucherre, Hamid Moha ou Maati, Nathalie Nasr, Amélie Pinard, Alexis Theron, Gaëlle Odelin, Jean-Pierre Desvignes, David Salgado, Gwenaëlle Collod-Béroud, Jean-François Avierinos, Guillaume Lebon, Stéphane Zaffran, Chris Jopling
bioRxiv 528588; doi: https://doi.org/10.1101/528588
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Piezo1 is required for outflow tract and aortic valve development
Adèle Faucherre, Hamid Moha ou Maati, Nathalie Nasr, Amélie Pinard, Alexis Theron, Gaëlle Odelin, Jean-Pierre Desvignes, David Salgado, Gwenaëlle Collod-Béroud, Jean-François Avierinos, Guillaume Lebon, Stéphane Zaffran, Chris Jopling
bioRxiv 528588; doi: https://doi.org/10.1101/528588

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