Thesis – Victor BERNARD

Role of hemodynamic forces and extracellular matrix in cardiac development and disease

Jury

• Romain CAPOULADE, Research scientist, Institut du Thorax, Nantes – Reviewer
• Robert KELLY, Research Director, IBDM, Marseille – Reviewer
• Anabela BENSIMON-BRITO, Research scientist, CBI, Toulouse – Examiner
• Florence RUGGIERO, Research Director, IGFL, Lyon – Examiner
• Pascal DE SANTA BARBARA, Research Director, PhyMedExp, University of Montpellier – Examiner
• Adèle FAUCHERRE, Research scientist, IGF, University of Montpellier – Thesis supervisor

Summary

Heart development relies on a close interplay between genetic programs and mechanical forces generated by blood flow. However, the mechanisms by which these forces regulate cardiac morphogenesis remain incompletely understood. During this thesis, we identified Crip2 as a novel cardiac mechanotransducer whose expression is regulated by hemodynamic forces through mechanosensitive ion channels. Loss of crip2 function in zebrafish and mice results in cardiovascular abnormalities, demonstrating its essential role in heart development. We also identified two rare CRIP2 variants in patients with congenital heart defects and developed an in vivo model to assess their pathogenicity. Investigation of the pathways regulated by Crip2 revealed a link with elastin (ELN), a major component of the cardiovascular extracellular matrix. Using an elna/b knockout zebrafish model, we demonstrated the pathogenicity of two human ELN variants, one of which is associated with bicuspid aortic valve, providing the first evidence of a direct link between ELN and this malformation. Together, these findings identify a novel molecular axis linking hemodynamic forces, mechanotransduction, and the extracellular matrix, while establishing new functional models for the interpretation of genetic variants involved in congenital heart defects.