Remodelling of supernumerary leaflet primordia leads to bicuspid aortic valve caused by loss of primary cilia

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F25%3A10499993" target="_blank" >RIV/00216208:11110/25:10499993 - isvavai.cz</a>

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=IQyYJxZCJY" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=IQyYJxZCJY</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1093/cvr/cvaf108" target="_blank" >10.1093/cvr/cvaf108</a>

Result language

angličtina

Original language name

Remodelling of supernumerary leaflet primordia leads to bicuspid aortic valve caused by loss of primary cilia

Original language description

Aims: Bicuspid aortic valve (BAV), where two valve leaflets are found instead of the usual three, affects 1-2% of the general population and is associated with significant morbidity and mortality. Despite its frequency, the majority of cases remain unexplained. This is, at least in part, because there are two types of valve leaflet primordia: endocardial cushions and intercalated valve swellings (ICVS). Moreover, multiple progenitors make distinct contributions to the formation of these primordia. Genomic studies in mouse and human have suggested a correlation between BAV and malfunctional primary cilia. However, the precise requirement for cilia during early embryonic valvulogenesis remains unknown. Methods and results: Here, we disrupted primary cilia by deleting the ciliary gene Ift88 in the main progenitor cells forming the aortic valve using specific Cre drivers: Wnt1-Cre for neural crest cells, Isl1-Cre for second heart field (SHF) cells, Tie2-Cre for endocardial-derived cells, and Tnnt2-Cre for direct-differentiating SHF in the ICVS. Loss of Ift88, and thus primary cilia, from neural crest cells and endocardium did not impact aortic valve formation. However, primary cilia were essential in SHF cells for aortic valve leaflet formation, with over half of Ift88f/f;Isl1-Cre mutants presenting with BAV. As the valve leaflets were forming, 50% of the Ift88f/f;Isl1-Cre mutants had two small leaflets in the position of the usual posterior leaflet, meaning that at this stage, the aortic valve was quadricuspid, which then remodelled to BAV by E15.5. Mechanistic studies demonstrated premature differentiation of SHF cells as the ICVS formed, leading to the formation of a broadened ICVS that formed two posterior leaflet precursors. This abnormality in the formation of the ICVS was associated with disruption of Notch-Jag1 signalling pathway, with Jag1f/f;Isl1-Cre mutants presenting with a similar phenotype. Conclusion: These data show that primary cilia, via the Notch-Jag1 signalling pathway, regulate differentiation of SHF cells in the aortic valve primordia. Additionally, we identify a mechanistic link between the developmental basis of quadricuspid and bicuspid arterial valve leaflets.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30106 - Anatomy and morphology (plant science to be 1.6)

Project

<a href="/en/project/GF24-12330K" target="_blank" >GF24-12330K: Top-NOTCH approach to pathological changes of congenital heart disease</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Cardiovascular Research

ISSN

0008-6363

e-ISSN

1755-3245

Volume of the periodical

121

Issue of the periodical within the volume

11

Country of publishing house

GB - UNITED KINGDOM

Number of pages

17

Pages from-to

1750-1766

UT code for WoS article

001518050200001

EID of the result in the Scopus database

2-s2.0-105017653978