Molecular Pathways Involved in RAGE Mediated Attenuation of Arteriogenesis

Abstract

The receptor for advanced glycation endproducts (RAGE) has been implicated in promoting vascular dysfunction through the activation of proinflammatory cascades and the induction of oxidative stress. Chronic activation of RAGE is associated with diabetes‐related vascular complications including coronary and peripheral vascular atherosclerosis and diabetic retinopathy. We have demonstrated that RAGE activation in monocytes and macrophages also regulates vascular remodeling in response to acute ischemia in a mouse model of hind‐limb ischemia. Lentiviral‐directed overexpression of RAGE in monocytes prevents the development of collateral vessels (arteriogenesis) in response to hind‐limb ischemia. To better understand the molecular mechanisms responsible for these observations, we have undertaken a cell culture approach to address the effect of monocyte ‐specific RAGE activation on the production of proarteriogenic and proangiogenic factors under hypoxic conditions and determine how chronic RAGE activation influences receptor recycling. We have generated soluble RAGE using a baculovirus system, which will provide a valuable reagent to evaluate RAGE signaling in response to hypoxic conditions. In addition, we are generating N‐terminal GFP‐tagged versions of the RAGE receptor that will allow us to evaluate RAGE receptor recycling following activation in a macrophage cell line.