Circadian regulation of vascular aging

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Vascular aging, the age-related molecular, structural and functional changes in the blood vessels, not only impairs normal vascular contraction and compliance but also increases the incidence of cardiovascular disease, including hypertension, coronary artery disease, heart failure, stroke and peripheral artery disease, as well as vascular complications in metabolic disease, such as diabetes. Therefore, better understanding of the molecular regulation of vascular aging may offer greater opportunities to identify promising targets for potential novel clinical interventions to prevent or retard vascular aging and age-related cardiovascular disease. The current application aims to fill the unmet scientific gaps to elucidate the molecular determinants in vascular aging. Vascular smooth muscle cell (VSMC) proliferation, migration, mineralization, extracellular matrix (ECM) deposition, and senescence contribute to age-related vascular structural and functional changes. As a result, increased medial and neointimal thickness, arterial stiffness, ECM degradation and calcification are manifestations of vascular aging, which promotes cardiovascular disease including atherosclerosis, hypertension, vascular calcification and stroke. We found that a key transcription factor Runx2 is elevated in an age-dependent manner, and SMC-specific deletion of Runx2 inhibited vascular complications that are more pronounced in aging, including atherosclerosis, neointimal formation and vascular calcification. Furthermore, Runx2 deficiency in VSMC inhibited the expression of VSMC matrix proteins and senescence, two hallmarks of VSMC aging, supporting a novel function of Runx2 in regulating vascular aging that is beyond its known function in regulating VSMC calcification. Mechanistically, we identified a previously unrecognized Runx2 oscillation in VSMC in culture as well as in mouse arteries in vivo. Runx2 oscillation in VSMC was associated with the oscillation of the key clock regulator, BMAL1, and the clock-regulated FOXO1. Coincidently, increased expression of BMAL1 and FOXO1 was demonstrated in aging arterials, similar to that of Runx2. With the use of loss-of-function approaches, our preliminary studies further demonstrated a causative function of circadian clock (BMAL1) and O-GlcNAcylation in regulating Runx2 expression. These results support the hypothesis that interplay of clock rhythm and protein O-GlcNAcylation promotes vascular aging through the FOXO/Runx2 signaling axis. Using novel inducible SMC-specific BMAL1, OGT and Runx2 deficient animal models, the proposal will characterize circadian clock-regulated vascular aging in mice (Aim 1); and delineate mechanisms underlying circadian regulation of vascular aging (Aim 2). Results from the proposed studies will develop a novel paradigm underlying vascular clock and O-GlcNAcylation regulation of the FOXO/Runx2 signaling axis in vascular aging, which will advance our understanding of basic mechanisms governing vascular aging. As vascular aging promotes many diseases, the novel mechanisms uncovered in this application should also have broad scientific and translational impact on increasing human lifespan and improving public health.