Identification of key patho-mechanisms underlying bicuspid aortic valve-related aortopathy using primary endothelial cells isolated from embryonic Madh6 pups.

Bicuspid aortic valve (BAV) is the most common congenital heart malformation affecting 1-2% of the population. This aortic valve defect is characterized by two leaflets instead of the normal three. While most BAV patients remain asymptomatic, approximately 35% of patients develop cardiovascular complications including dangerous thoracic aortic aneurysms (TAAs) and lethal dissections. To date, BAV/TAA remains a serious health problem due to the high heritability of BAV and no curative pharmacological therapies for (BAV-related) TAA are currently available. In 2017, we demonstrated a significant enrichment of deleterious SMAD6 variants in BAV/TAA patients compared to the general population. SMAD6 is highly expressed in the cardiovascular system, particularly in endothelial cells. It encode an inhibitory SMAD protein which negatively regulates BMP and TGF-β signaling. Both pathways have been previously and independently described to associate with defects of the aortic valve and thoracic aortic wall including aneurysms. Furthermore, endothelial cell dysfunction is gaining momentum as potential disease contributor, or even disease driver in both valve and aortic aneurysmal disease. Our knowledge on genetic SMAD6 data will serve as the perfect starting point to significantly expand our understanding on the mechanistic insights on BAV/TAA disease. Hence, this projects aims to relate SMAD6 deficiency to abnormalities of the aortic valve and wall by interrogating distinctive cellular and molecular processes in embryonic endothelial cells isolated from a Madh6 mouse model. The anticipated results will aid to elucidate the pathogenesis as well as initiate the identification of novel therapeutic targets for (BAV-related) TAA.

Keywords:PATHOMECHANISM, GENE DEFECT, BICUSPID AORTIC VALVE-RELATED AORTOPATHY

Disciplines:Genetics