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Science 300 (5617): 329-332

Copyright © 2003 by the American Association for the Advancement of Science

LRP: Role in Vascular Wall Integrity and Protection from Atherosclerosis

Philippe Boucher,1* Michael Gotthardt,1* Wei-Ping Li,2 Richard G. W. Anderson,2 Joachim Herz1dagger

Vascular smooth muscle cell (SMC) proliferation and migration are important events in the development of atherosclerosis. The low-density lipoprotein receptor-related protein (LRP1) mediates suppression of SMC migration induced by platelet-derived growth factor (PDGF). Here we show that LRP1 forms a complex with the PDGF receptor (PDGFR). Inactivation of LRP1 in vascular SMCs of mice causes PDGFR overexpression and abnormal activation of PDGFR signaling, resulting in disruption of the elastic layer, SMC proliferation, aneurysm formation, and marked susceptibility to cholesterol-induced atherosclerosis. The development of these abnormalities was reduced by treatment with Gleevec, an inhibitor of PDGF signaling. Thus, LRP1 has a pivotal role in protecting vascular wall integrity and preventing atherosclerosis by controlling PDGFR activation.

1 Department of Molecular Genetics,
2 Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9046, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: Joachim.Herz{at}UTSouthwestern.edu



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Macrophage Low-Density Lipoprotein Receptor-Related Protein Deficiency Enhances Atherosclerosis in ApoE/LDLR Double Knockout Mice.
L. Hu, L.S.M. Boesten, P. May, J. Herz, N. Bovenschen, M.V. Huisman, J.F.P. Berbee, L.M. Havekes, B.J.M. van Vlijmen, and J.T. Tamsma (2006)
Arterioscler Thromb Vasc Biol 26, 2710-2715
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Neurofibromin is a novel regulator of RAS-induced signals in primary vascular smooth muscle cells.
F. Li, A. M. Munchhof, H. A. White, L. E. Mead, T. R. Krier, A. Fenoglio, S. Chen, X. Wu, S. Cai, F.-C. Yang, et al. (2006)
Hum. Mol. Genet. 15, 1921-1930
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Modulation of Smooth Muscle Cell Migration by Members of the Low-Density Lipoprotein Receptor Family.
H. Bujo and Y. Saito (2006)
Arterioscler Thromb Vasc Biol 26, 1246-1252
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Regulation of the Composition of the Extracellular Matrix by Low Density Lipoprotein Receptor-related Protein-1: ACTIVITIES BASED ON REGULATION OF mRNA EXPRESSION.
A. Gaultier, A. M. Salicioni, S. Arandjelovic, and S. L. Gonias (2006)
J. Biol. Chem. 281, 7332-7340
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Uremia-Specific Effects in the Arterial Media During Development of Uremic Atherosclerosis in Apolipoprotein E-Deficient Mice.
S. Bro, R. Borup, C. B. Andersen, F. Moeller, K. Olgaard, and L. B. Nielsen (2006)
Arterioscler Thromb Vasc Biol 26, 570-575
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Mutant Lrp1 Knock-In Mice Generated by Recombinase-Mediated Cassette Exchange Reveal Differential Importance of the NPXY Motifs in the Intracellular Domain of LRP1 for Normal Fetal Development.
A. J. M. Roebroek, S. Reekmans, A. Lauwers, N. Feyaerts, L. Smeijers, and D. Hartmann (2006)
Mol. Cell. Biol. 26, 605-616
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Decreased Neurotrophin TrkB Receptor Expression Reduces Lesion Size in the Apolipoprotein E-Null Mutant Mouse.
R. Kraemer, P. J. Baker, K. C. Kent, Y. Ye, J. J. Han, R. Tejada, M. Silane, R. Upmacis, R. Deeb, Y. Chen, et al. (2005)
Circulation 112, 3644-3653
   Abstract »    Full Text »    PDF »
Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice.
E. B. Johnson, R. E. Hammer, and J. Herz (2005)
Hum. Mol. Genet. 14, 3523-3538
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The Platelet-derived Growth Factor Receptor-{beta} Phosphorylates and Activates G Protein-coupled Receptor Kinase-2: A MECHANISM FOR FEEDBACK INHIBITION.
J.-H. Wu, R. Goswami, L. K. Kim, W. E. Miller, K. Peppel, and N. J. Freedman (2005)
J. Biol. Chem. 280, 31027-31035
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The apoE isoform binding properties of the VLDL receptor reveal marked differences from LRP and the LDL receptor.
J. Ruiz, D. Kouiavskaia, M. Migliorini, S. Robinson, E. L. Saenko, N. Gorlatova, D. Li, D. Lawrence, B. T. Hyman, K. H. Weisgraber, et al. (2005)
J. Lipid Res. 46, 1721-1731
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Platelet-derived Growth Factor Receptor-{beta} (PDGFR-{beta}) Activation Promotes Its Association with the Low Density Lipoprotein Receptor-related Protein (LRP): EVIDENCE FOR CO-RECEPTOR FUNCTION.
C. S. Newton, E. Loukinova, I. Mikhailenko, S. Ranganathan, Y. Gao, C. Haudenschild, and D. K. Strickland (2005)
J. Biol. Chem. 280, 27872-27878
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Structural Requirements for Activation of Latent Platelet-derived Growth Factor CC by Tissue Plasminogen Activator.
L. Fredriksson, M. Ehnman, C. Fieber, and U. Eriksson (2005)
J. Biol. Chem. 280, 26856-26862
   Abstract »    Full Text »    PDF »
Low Density Lipoprotein Receptor-related Protein 1 (LRP1) Controls Endocytosis and c-CBL-mediated Ubiquitination of the Platelet-derived Growth Factor Receptor {beta} (PDGFR{beta}).
Y. Takayama, P. May, R. G. W. Anderson, and J. Herz (2005)
J. Biol. Chem. 280, 18504-18510
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Antisense oligodeoxyribonucleotide as to the growth factor midkine suppresses neointima formation induced by balloon injury.
K. Hayashi, H. Banno, K. Kadomatsu, Y. Takei, K. Komori, and T. Muramatsu (2005)
Am J Physiol Heart Circ Physiol 288, H2203-H2209
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An MT1-MMP-PDGF receptor-{beta} axis regulates mural cell investment of the microvasculature.
K. Lehti, E. Allen, H. Birkedal-Hansen, K. Holmbeck, Y. Miyake, T.-H. Chun, and S. J. Weiss (2005)
Genes & Dev. 19, 979-991
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Adipose tissue gene expression profiling reveals distinct molecular pathways that define visceral adiposity in offspring of maternal protein-restricted rats.
H. Guan, E. Arany, J. P. van Beek, A. Chamson-Reig, S. Thyssen, D. J. Hill, and K. Yang (2005)
Am J Physiol Endocrinol Metab 288, E663-E673
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LDL Receptor-Related Protein and the Vascular Wall: Implications for Atherothrombosis.
V. Llorente-Cortes and L. Badimon (2005)
Arterioscler Thromb Vasc Biol 25, 497-504
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Gallic Acid Antagonizes P-Selectin-Mediated Platelet-Leukocyte Interactions: Implications for the French Paradox.
C. C.M. Appeldoorn, A. Bonnefoy, B. C.H. Lutters, K. Daenens, T. J.C. van Berkel, M. F. Hoylaerts, and E. A.L. Biessen (2005)
Circulation 111, 106-112
   Abstract »    Full Text »    PDF »
Absence of p21Waf1/Cip1/Sdi1 Modulates Macrophage Differentiation and Inflammatory Response and Protects Against Atherosclerosis.
A. J. Merched and L. Chan (2004)
Circulation 110, 3830-3841
   Abstract »    Full Text »    PDF »
Regulation of Vascular Calcification by Osteoclast Regulatory Factors RANKL and Osteoprotegerin.
P. Collin-Osdoby (2004)
Circ. Res. 95, 1046-1057
   Abstract »    Full Text »    PDF »
Neuronal LRP1 Functionally Associates with Postsynaptic Proteins and Is Required for Normal Motor Function in Mice.
P. May, A. Rohlmann, H. H. Bock, K. Zurhove, J. D. Marth, E. D. Schomburg, J. L. Noebels, U. Beffert, J. D. Sweatt, E. J. Weeber, et al. (2004)
Mol. Cell. Biol. 24, 8872-8883
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