Project Summary/Abstract In humans, large conduit arteries lose elasticity and thicken with aging and other pathological conditions leading to central arterial stiffening and hypertension. The prevalence of arterial stiffness and hypertension increases with age. Currently, there is no effective intervention for aging-associated arterial stiffness. Aging is an important risk factor for cardiovascular disease. KDM6A is a recently- discovered histone demethylase. Mutation of this gene causes severe defective embryogenesis. The objective of the proposed research is to investigate if KDM6A in vascular smooth muscle cells (VSMCs) plays a role in the regulation of arterial compliance and structure and further investigate if KDM6A is involved in aging-associated arterial stiffness and hypertension. This objective will be achieved by pursuing two coherent specific aims using a combination of several cutting-edge approaches. The two specific aims are: (1) Determine if KDM6A in VSMCs plays a role in the regulation of arterial compliance and structure. (2) Investigate if KDM6A in VSMCs is involved in the aging-related arterial stiffness and hypertension. The proposed work is innovative and significant because it utilizes state-of-the-art approaches to address aging-related arterial stiffness which affects a large population but remains poorly understood. The results will reveal novel molecular mechanisms that mediate the pathogenesis of aging-associated arterial remodeling and stiffness and hypertension. Completion of this project may provide new insights into preventive and therapeutic strategies for aging-associated arterial stiffness and hypertension.