Role of LRP1 in Angiotensin Signaling and Vascular Remodeling

University Of Maryland Baltimore, Baltimore MD

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Abstract

? DESCRIPTION (provided by applicant): The low-density lipoprotein receptor-related protein 1 (LRP1) is a large endocytic receptor that recognizes numerous, unrelated ligands; however, LRP1 also functions in signal transduction pathways and can interact with other cellular receptors. Highly expressed in vascular smooth muscle cells (VSMC), recent studies reveal an important role for LRP1 in embryonic vascular development. LRP1 maintains vascular wall integrity and conveys atheroprotective effects, and deletion of LRP1 in VSMC results in disruption of elastic layers, tortuous aorta, aneurysm formation, increased susceptibility to atherosclerosis, and increased neointima formation upon vascular injury. Currently, the mechanism by which LRP1 modulates these processes is unknown. Using the well characterized carotid artery ligation model to investigate vascular remodeling and employing mice in which LRP1 is selectively deleted from VSMC (smLRP1-/-), preliminary studies reveal a major role for LRP1 in attenuating injury-induced neointima formation. To define a potential mechanism by which LRP1 regulates vascular remodeling, studies have been focused on the renin-angiotensin-aldosterone system, a hormone system that regulates blood pressure and vascular remodeling. Excessive intimal hyperplasia is observed upon vascular injury in smLRP1-/- mice and is correlated with elevated levels of transforming growth factor ? (TGF-?) signaling; furthermore, neointima formation is completely ablated with losartan treatment, an angiotensin II type 1 receptor antagonist. The central hypothesis of this application is that LRP1 regulates vascular remodeling by modulating angiotensin II-mediated signaling. This hypothesis will be tested by the following specific aims: (1) Determine if smooth muscle LRP1 protects against injury-induced intimal hyperplasia in an angiotensin II-dependent mechanism and (2) Define the mechanisms by which LRP1 attenuates the angiotensin II-mediated signaling pathway. Studies will be performed on LRP1+/+ and smLRP1-/- mice subjected to vascular injury and treated with various anti-hypertensive drugs or a TGF-? neutralizing antibody. Blood pressure will be monitored throughout treatment and carotid arteries will be subsequently analyzed by histology, immunohistochemistry, western blotting, and qRT-PCR. Migration and proliferation studies utilizing pathway-specific inhibitors will also be performed on VSMC isolated from LRP1+/+ and smLRP1-/- mice. The overall objective of this application is to determine the specific mechanism by which LRP1 regulates vascular remodeling. Defining the role of LRP1 in vascular remodeling may reveal novel strategies to prevent or retard the development of stenosis, reduce the incidence of restenosis in patients, and improve overall cardiovascular health.