Published online before print May 27, 2004, doi: 10.1161/01.ATV.0000133607.80554.09
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© 2004 American Heart Association, Inc.
Vascular Biology |
LRP1B Attenuates the Migration of Smooth Muscle Cells by Reducing Membrane Localization of Urokinase and PDGF Receptors
From the Departments of Clinical Cell Biology (K. Tanaga, Y.Z., T.K., S.H., K. Takahashi, Y.S.) and Genome Research and Clinical Application (H.B.), Chiba University Graduate School of Medicine, Chiba, Japan; Omigawa Hospital (M.I., K.M.), Omigawa, Japan; and the Department of Molecular Genetics (S.H., W.J.S.), Biocenter and University of Vienna, Vienna, Austria.
Correspondence to Hideaki Bujo, Department of Genome Research and Clinical Application, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail hbujo{at}faculty.chiba-u.jp
Objective— Studies on the involvement of low-density lipoprotein receptor relatives (LRs) in atherosclerosis have recently gained new focus because of the specific expression of certain of these receptors in the thickened intima. Here, we show that LRP1B, a member of LRs, modulates the migration of smooth muscle cells (SMCs) by increasing the degradation of membrane receptors, urokinase-type plasminogen activator receptor (uPAR), and platelet-derived growth factor receptor (PDGFR) ß.
Methods and Results— Immunohistochemistry showed that LRP1B expression in human coronary arteries is localized to the intimal SMCs near the plaque surface as well as to medial SMCs. LRP1B expression levels in cultured SMCs increase at the late phase of proliferation. Cell surface and internalization assays, in combination with coimmunoprecipitation experiments, showed that LRP1B binds and internalizes uPAR. Metabolic labeling analysis demonstrated that anti-LRP1B IgY decreased the catabolism of uPAR. In addition, the anti-LRP1B antibody raised PDGFRß protein and PDGFR-mediated phosphorylation levels of ERK1/2. Finally, the anti-LRP1B IgY enhanced the migration and invasion of SMCs in the presence of PDGF-BB.
Conclusions— LRP1B modulates the catabolism of uPAR and PDGFR, affecting the migration of SMCs. This functional characterization of LRP1B opens novel avenues for elucidating the (patho)physiological significance of SMC migration in atheromatous plaques.
LDL receptor relatives (LRs) in atherosclerosis have gained new focus because of the specific expression of these receptors in the thickened intima. LRP1B modulates the migration of SMCs by increasing the degradation of uPAR and PDGFR. This functional characterization of LRP1B elucidates the (patho)physiological significance of SMC migration in plaques.
Key Words: smooth muscle cells • LRP1B • PDGF receptor • uPA receptor • migration
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