Role of LRP1 in Protecting the Vasculature
Since the early studies of Russell Ross, numerous investigators have confirmed that inflammation is a driving force behind chronic diseases such as atherosclerosis, and key to this process is the recruitment and activation of macrophages. Our studies reveal that the LDL receptor-related protein (LRP1) plays an important role in macrophage biology by regulating the adhesive properties of the integrin αMß2. LRP1 is a large endocytic and signaling receptor that is widely expressed and mediates the endocytosis and subsequent degradation of several ligands. Deletion of the Lrp1 gene is lethal in mice, and genome wide association studies reveal that the Lrp1 gene represents a susceptibility locus for migraine, for elevated plasma lipids, and for coronary heart disease. LRP1 is abundantly expressed in macrophages where it functions to protect the vasculature from the development of disease. By employing macrophage specific knockout mice (macLRP1-/- mice) we discovered that LRP1 expressed in these cells protects the vasculature from excessive remodeling upon injury by regulating the TGFß signaling pathway and by influencing vascular smooth muscle cell (SMC) recruitment into the developing neo-intima. It is well established that an important contribution to cardiovascular diseases is the transdifferentiation of SMC. Under normal physiological conditions, SMC are fully differentiated and in a contractile phenotype. However, under pathological conditions SMC switch to a proliferative and migratory phenotype and contribute to lesion development in atherosclerosis and/or neo-intima formation. Significant effort is underway to define molecular mechanisms regulating SMC transdifferentiation, and substantial evidence suggests an important role for the LDL receptor related protein 1 (LRP1) in this process by modulating the PDGF signaling pathway. Our data in SMC LRP1 deficient mice (smLRP1-/-) reveal that LRP1 modulates SMC transdifferentiation and regulates pathways relevant to neo-intima and aneurysm formation.
- © 2011 by American Heart Association, Inc.