Novel Regulators of Vascular Disease

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Novel Regulators of Vascular Disease Between 20 and 90 years of age, arterial wall intimal-media thickness increases, promoting arterial stiffness. Increased conduit artery stiffness is a key factor in the pathogenesis of aging-associated diseases such as systolic hypertension, cerebrovascular, cardiovascular, renovascular, and peripheral vascular diseases - all represent a significant burden affecting the Veteran population. This VA-PPA is a unique opportunity to bring together four VA investigators to study the pathobiology of conduit artery stiffness. A series of three inter-related projects and a state-of-the-art animal vascular phenotyping core facility will focus on the common theme of vascular dysfunction associated with matrix protein deposition and medial calcification, two factors known to increase arterial stiffness during aging and chronic kidney disease (CKD). The specific objectives of the three Projects and Core are to: 1. Define the mechanisms by which the aging process reduces endothelial nitric oxide (NO) synthase function and alters vascular production of Transforming Growth Factor-ss (TGF-ss) to facilitate the development of arterial stiffness with aging (Project 1: Molecular Mechanisms of Aging on Vascular Function; PI: Paul Sanders). The working hypothesis of this project is the ratio of active TGF-ss to NO is a critical, modifiable determinant of arterial stiffness of aging. 2. Determine the role of Runx2 in regulating arterial stiffening and elucidate the molecular mechanisms, using a novel smooth muscle-specific Runx2 knockout mouse model (Project 2: Molecular Mechanisms Underlying Arterial Stiffening; PI: Yabing Chen). The working hypothesis of this project is that a high salt intake induces the expression of Runx2 in VSMC, which initiates VSMC calcification and promotes arterial stiffening. 3. Define the role of the heme oxygenase-1 (HO-1)/ferritin system in the prevention of vascular calcification through downregulation of Runx2 and TGF-ss ((Project 3: Role of HO-1/Ferritin in Vascular Calcification During Aging; PI: Anupam Agarwal). Experiments will test the working hypothesis that induction of the HO-1/ferritin system prevents vascular calcification through downregulation of Runx2 and TGF-¿. 4. Support a state-of-the-art core facility (Animal Vascular Phenotyping Core; Director: Edgar Jaimes) designed to provide detailed structure-function analyses of arterial stiffness and vascular calcification. The core will consist of a vascular physiology subcore for radiotelemetry, high frequency vascular ultrasound, micro-CT and endothelial function (myography); and a molecular pathology subcore for histology, immunohistochemistry and image analysis. The core will bring to the Birmingham VA Medical Center (BVAMC) new technology to study vascular biology. The long-term goal of this research effort is to lay the essential groundwork necessary to translate the findings to improved cardiovascular outcomes in aging and CKD and further build the research capacity at the BVAMC.