A role for primary cilia in aortic valve development and disease

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Genetics

Background:

• Bicuspid aortic valve (BAV) is the most common congenital heart defect, affecting 0.5-1.2% of the population.
• BAV inheritance is complex, with no single gene model explaining its etiology.
• Ciliopathies, disorders of primary cilia, frequently present with BAV, suggesting a role for cilia in heart development.

Purpose of the Study:

• To investigate the role of primary cilia in aortic valve development.
• To determine if primary cilia dysfunction contributes to BAV disease.

Main Methods:

• Examined primary cilia expression in aortic valve mesenchymal cells during embryonic development.
• Genetically ablated the ciliogenesis gene Ift88 to assess the functional impact of cilia loss.
• Analyzed extracellular matrix (ECM) production and aortic valve morphology in Ift88-deficient embryos.

Main Results:

• Primary cilia are present on aortic valve mesenchymal cells during development and are lost upon differentiation.
• Loss of Ift88 abrogated primary cilia and led to increased fibrogenic ECM production.
• Aortic valves in Ift88-deficient embryos exhibited disrupted ECM stratification and a high incidence of BAV phenotype at birth.

Conclusions:

• Primary cilia act as a novel cellular mechanism to regulate ECM production during aortic valve development.
• These findings implicate primary cilia broadly in the etiology of human BAV disease.