LRP1 Regulates Architecture of the Vascular Wall by Controlling PDGFRβ-Dependent Phosphatidylinositol 3-Kinase Activation

Background: Low density lipoprotein receptor-related protein 1 (LRP1) protects against atherosclerosis by regulating the activation of platelet-derived growth factor receptor beta (PDGFR beta) in vascular smooth muscle cells (SMCs). Activated PDGFR beta undergoes tyrosine phosphorylation and subsequently interacts with various signaling molecules, including phosphatidylinositol 3-kinase (PI3K), which binds to the phosphorylated tyrosine 739/750 residues in mice, and thus regulates actin polymerization and cell movement. Methods and Principal Findings: In this study, we found disorganized actin in the form of membrane ruffling and enhanced cell migration in LRP1-deficient (LRP1-/-) SMCs. Marfan syndrome-like phenotypes such as tortuous aortas, disrupted elastic layers and abnormally activated transforming growth factor beta (TGF beta) signaling are present in smooth muscle-specific LRP1 knockout (smLRP1-/-) mice. To investigate the role of LRP1-regulated PI3K activation by PDGFR beta in atherogenesis, we generated a strain of smLRP1-/- mice in which tyrosine 739/750 of the PDGFR beta had been mutated to phenylalanines (PDGFR beta F2/F2). Spontaneous atherosclerosis was significantly reduced in the absence of hypercholesterolemia in these mice compared to smLRP1-/- animals that express wild type PDGFR. Normal actin organization was restored and spontaneous SMC migration as well as PDGF-BB-induced chemotaxis was dramatically reduced, despite continued overactivation of TGF beta signaling, as indicated by high levels of nuclear phospho-Smad2. Conclusions and Significance: Our data suggest that LRP1 regulates actin organization and cell migration by controlling PDGFR beta-dependent activation of PI3K. TGF beta activation alone is not sufficient for the expression of the Marfan-like vascular phenotype. Thus, regulation of PI3 Kinase by PDGFR beta is essential for maintaining vascular integrity, and for the prevention of atherosclerosis as well as Marfan syndrome.