The Role of Hydrogen Peroxide in RAGE Expression in Collateral Vessel Formation

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 DESCRIPTION (provided by applicant): Both coronary artery and peripheral vascular disease are growing health concerns that can lead to impaired blood flow and tissue ischemia, though neovascularization and growth of collateral vessels can help to restore blood flow and preserve the tissue improving outcomes. Collateral formation includes both angiogenesis and arteriogenesis and is a complex process with many coordinating parts including inflammatory signaling and cell proliferation and migration. The balance of these inflammatory responses is important since too little or too much can impair vessel growth. One factor that has been associated with negative effects on collateral growth and may exacerbate the negative effects of inflammatory signals is the receptor for advanced glycation end products (RAGE); however, the cellular source and the mechanism of its regulation in ischemic regions is not fully understood. The preliminary data show increases in RAGE expression mediated by hydrogen peroxide (H2O2) in an ischemia model and that RAGE has a negative effect on collateral formation in a non-diabetic state. We hypothesized that satellite cells are a major source of RAGE in ischemia and that RAGE expression is H2O2-mediated. To test this hypothesis we plan to use both in vivo and in vitro models. Aim 1 will use a mouse hind limb ischemia (HLI) model to confirm if increased RAGE expression is upregulated in response to H2O2 and confirm that satellite cells express RAGE in response to H2O2. This aim will also investigate the mechanisms by which H2O2 mediates RAGE expression. In Aim 2, we will investigate differences in the production of several factors that mediate collateral growth in wildtype and RAGE knockout satellite cells. The effects of the different cell types on cell migration and proliferation will be studied as well. Fially in Aim 3, we will study the specific role of H2O2-mediated RAGE expression in the satellite cells using a transgenic mouse with satellite cell specific overexpression of catalase a H2O2 scavenger (TgCat-pax7). These studies will advance the understanding of the role of RAGE and its regulation. It is critical to understand how RAGE expression is regulated in non-diabetic ischemia and what the cellular sources of RAGE are in the ischemic setting because manipulating its regulation could help improve collateral formation and improve blood flow and clinical outcomes for patients with ischemic disease.