Fibrocalcific Aortic Valve Stenosis (AVS), characterized by a narrowing of the aortic valve opening, leads to an obstacle to the blood flow through the aortic valve during left ventricular ejection. In industrialized countries, this disease affects 2 to 6% of people aged above 65 years and its prevalence is likely to double within the next 50 years due to an increasingly ageing population. Initially described as a degenerative process related to valve repeated aggression by blood flow, the AVS pathophysiology is now understood to be an active process akin to atherosclerosis involving initiating factors, endothelial dysfunction, inflammatory responses and angiogenesis leading to valve remodeling and calcification. Although important progress has been made in understanding the pathophysiology of this disease, there is currently no pharmacological treatment available to alter the natural course of the disease. While the onset of symptoms indicates a poor prognosis, the only effective therapy for SVA is valve replacement by a mechanical prosthesis or bioprosthesis. In industrialized countries, bioprosthesis are mainly used. These prostheses do not require anticoagulant treatment but present limited lifespan (10 years), mainly due to progressive calcification and degeneration of the tissue. The mechanisms involved in this context seem close to those observed in AVS. A healthy aortic valve is mainly composed of valvular interstitial cells (VIC) which are highly dynamic and plastic. Thus, these cells can differentiate into calcific osteoblast-like cells or into perivascular cells, as shown in our preliminary results. A preliminary analysis of normal and fibrocalcific human aortic valves and VIC isolated from these valves indicates that the retinoic acid pathway via its nuclear receptors is implicated in the process of AV calcification. The objectives of the RETINAVS project are to study more precisely the role of the retinoic acid pathway in AVS development and bioprosthesis degeneration by focusing on the calcification and angiogenesis processes, to highlight new factors modulating these processes and to identify, in the retinoic acid pathway, innovative pharmacological targets that will be validated by in vitro and in vivo preclinical approaches (animal models of aortic valve calcification and bioprosthesis degeneration). The RETINAVS project combines 3 major assets : 1) an ongoing collection of human fibrocalcific and normal aortic valves but also explanted bioprostheses. Studies on normal valves are very scarce in the literature and the access to such samples is a great advance to better understand the processes underlying the progression of the disease, from normal to pathological valves, 2) the gathering of biologists, cardiologists specialists in atherosclerosis, AVS and angiogenesis, cardiac surgeons specialists in valvulopathy and basic researchers involved in the deciphering of the role of the retinoid acid pathway and nuclear receptors in cardiovascular diseases (UMR Inserm 1011) and in progenitor cells characterization, of their angiogenic potential and ability to induce vascular remodeling (UMR-S Inserm 1140). The successful collaboration between partners for almost 10 years ensures the success of this ambitious translational project at the interface between fundamental and clinical research; 3) the combination of studies on human samples and animal models already developed in 2 teams. Our ambition is to identify retinoic acid and its associated pathways as potential new therapeutic targets in AVS and to define a new paradigm in pathophysiology of this disease and valvular bioprosthesis degeneration that represents a real challenge of public health.