Cellular and molecular mechanisms of human aortic valve calcification

Because human aortic valve calcification can only be treated by valve replacement, it is a priority and a rapidly evolving field addressing the cellular and molecular mechanisms of calcific aortic valve disease. By elucidating these mechanisms, we may open up for new pharmacological therapies. Therefore, the overarching hypothesis which prompted us to launch the present research project was: when understanding the cellular and molecular mechanisms of aortic valve calcification it may be possible to pharmacologically intervene and inhibit the process. We performed experiments on primary cells from human aortic valves which is at the time being the preferred model of aortic valve calcification. Firstly, we optimized and established the methods to study human aortic valve calcification in vitro. Next, we studied the interplay between different factors involved in aortic valve calcification, including mechanical stress, inflammatory signals and composition of extracellular matrix. We found that inflammation and mechanical stretch synergistically increase calcification and osteogenic gene expression in aortic valve interstitial cells cultured on collagen coating, representing the extracellular matrix of the aortic side of the valve, which is where calcification invariably occurs. Additionally, we compared the cells from healthy and calcified aortic valves, and found that the capacity to differentiate into other cell types (stemness) is limited in cells from calcified valves, while the cells from healthy valves have higher multipotent differentiation potential, higher expression of stem cell-associated markers and a higher ability to proliferate. Finally, we suggested the possible therapeutic treatment that may prevent or inhibit ongoing calcification in the aortic valves. The results of this project are important to take into consideration while developing and testing pharmaceutical treatment for aortic valve calcification