Abstract Body (Do not enter title and authors here): Aortic valve stenosis (AS) is characterized by a disruption of the intricate structure of the valve through mineralization and fibrosis of valve cusps. The prevalence of calcific aortic valve disease (CAVD) increases with age, ranging from 3 to 5% in the population over 65 years. Multiple risk factors have been linked to CAVD, such as age, male gender, smoking, hypertension, obesity, diabetes, and metabolic syndrome. Metalloproteinase, or TNF-α converting enzyme (TACE), is required in valvular endothelial cells to regulate cell content and extracellular matrix composition and organization in semilunar valve remodeling and homeostasis. Aortic valve cusps from TACE mutant mice are hyperplastic and expand the glycosaminoglycan-rich component, with most adults exhibiting aberrant compartmentalization of versican and increased collagen deposition. Delta-like homolog (Dlk1) is a substrate of TACE. Dlk1 can be proteolytically cleaved within the juxta-membrane region by TACE, releasing the extracellular part of Dlk1 as a soluble fragment known as fetal antigen 1 (FA1). Dlk1-/- an increased fat mass characterizes mice because of adipocyte hypertrophy rather than hyperplasia. Our Hypothesis is that enhanced TACE activity and increased soluble Dlk1 modulate ECM remodeling and lipid retention, affecting β-integrin expression and disturbing cytoskeleton organization. Methods: we used DLK1 mutant mice, echocardiography, and a super-resolution microscope to examine the structure of valvular cells. Results: our preliminary data showed that Dlk1-/- aortic valves were thicker and retained more oxLDL than WT mice. In addition, the deletion of Dlk1 was associated with β-integrin downregulation and increased intracellular calcium in the aortic valve. Cytoskeleton disorganization destabilized the normal intracellular calcium influx. This chronic increase in intracellular calcium activated apoptosis of valve cells. Hence, Dlk1 may act as a critical regulator of aortic valve calcification. As such, Dlk1 may represent an attractive novel target for assessing the progression and treatment of AS.