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

被引：57

作者：

Zhou, Li

Takayama, Yoshiharu

Boucher, Philippe

Tallquist, Michelle D.

Herz, Joachim

机构：

[1] Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX

[2] Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX

[3] Department of Pharmacology, University of Strasbourg, Strasbourg

来源：

PLOS ONE | 2009年 / 4卷 / 09期

关键词：

RECEPTOR-RELATED PROTEIN; PHOSPHOLIPASE-C-GAMMA; PHOSPHOINOSITIDE; 3-KINASE; MARFAN-SYNDROME; TGF-BETA; GROWTH-INHIBITION; MOUSE MODEL; PATHOGENESIS; CELLS; INVOLVEMENT;

D O I：

10.1371/journal.pone.0006922

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

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页数：11

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共 46 条

[31] Activation of Rac1 by phosphatidylinositol 3-kinase in vivo:: role in activation of mitogen-activated protein kinase (MAPK) pathways and retinoic acid-induced neuronal differentiation of SH-SY5Y cells [J].

Pan, J ;

Kao, YL ;

Joshi, S ;

Jeetendran, S ;

DiPette, D ;

Singh, US .

JOURNAL OF NEUROCHEMISTRY, 2005, 93 (03) :571-583

[32] Prolongation of insulin-induced activation of mitogen-activated protein kinases ERK 1/2 and phosphatidylinositol 3-kinase by vanadyl sulfate, a protein tyrosine phosphatase inhibitor [J].

Théberge, JF ;

Mehdi, MZ ;

Pandey, SK ;

Srivastava, AK .

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 2003, 420 (01) :9-17

[33] Role of phosphatidylinositol 3-kinase/Akt pathway in angiotensin II and insulin-like growth factor-1 modulation of nitric oxide synthase in vascular smooth muscle cells [J].

Isenovic, ER ;

Meng, Y ;

Divald, A ;

Milivojevic, N ;

Sowers, JR .

ENDOCRINE, 2002, 19 (03) :287-291

[34] Pituitary Adenylate Cyclase-activating Polypeptide (PACAP)/PAC1HOP1 Receptor Activation Coordinates Multiple Neurotrophic Signaling Pathways Akt ACTIVATION THROUGH PHOSPHATIDYLINOSITOL 3-KINASE γ AND VESICLE ENDOCYTOSIS FOR NEURONAL SURVIVAL [J].

May, Victor ;

Lutz, Eve ;

MacKenzie, Christopher ;

Schutz, Kristin C. ;

Dozark, Kate ;

Braas, Karen M. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (13) :9749-9761

[35] Stromal Cell-Derived Factor-1 Promotes Endothelial Colony-Forming Cell Migration Through the Ca2+-Dependent Activation of the Extracellular Signal-Regulated Kinase 1/2 and Phosphoinositide 3-Kinase/AKT Pathways [J].

Zuccolo, Estella ;

Di Buduo, Christian ;

Lodola, Francesco ;

Orecchioni, Stefania ;

Scarpellino, Giorgia ;

Kheder, Dlzar Ali ;

Poletto, Valentina ;

Guerra, Germano ;

Bertolini, Francesco ;

Balduini, Alessandra ;

Rosti, Vittorio ;

Moccia, Francesco .

STEM CELLS AND DEVELOPMENT, 2018, 27 (01) :23-34

[36] Exercise Training Stimulates Ischemia-Induced Neovascularization via Phosphatidylinositol 3-Kinase/Akt-Dependent Hypoxia-Induced Factor-1α Reactivation in Mice of Advanced Age [J].

Cheng, Xian Wu ;

Kuzuya, Masafumi ;

Kim, Weon ;

Song, Haizhen ;

Hu, Lina ;

Inoue, Aiko ;

Nakamura, Kae ;

Di, Qun ;

Sasaki, Takeshi ;

Tsuzuki, Michitaka ;

Shi, Guo-Ping ;

Okumura, Kenji ;

Murohara, Toyoaki .

CIRCULATION, 2010, 122 (07) :707-716

[37] Serotonin-induced growth of pulmonary artery smooth muscle requires activation of phosphatidylinositol 3-kinase/serine-threonine protein kinase B/mammalian target of rapamycin/p70 ribosomal S6 kinase 1 [J].

Liu, YL ;

Fanburg, BL .

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 2006, 34 (02) :182-191

[38] Modulation in Activation and Expression of Phosphatase and Tensin Homolog on Chromosome Ten, Akt1, and 3-Phosphoinositide-Dependent Kinase 1: Further Evidence Demonstrating Altered Phosphoinositide 3-Kinase Signaling in Postmortem Brain of Suicide Subjects [J].

Dwivedi, Yogesh ;

Rizavi, Hooriyah S. ;

Zhang, Hui ;

Roberts, Rosalinda C. ;

Conley, Robert R. ;

Pandey, Ghanshyam N. .

BIOLOGICAL PSYCHIATRY, 2010, 67 (11) :1017-1025

[39] Estrogen Activation of G-Protein-Coupled Estrogen Receptor 1 Regulates Phosphoinositide 3-Kinase and mTOR Signaling to Promote Liver Growth in Zebrafish and Proliferation of Human Hepatocytes [J].

Chaturantabut, Saireudee ;

Shwartz, Arkadi ;

Evason, Kimberley J. ;

Cox, Andrew G. ;

Labella, Kyle ;

Schepers, Arnout G. ;

Yang, Song ;

Acuna, Mariana ;

Houvras, Yariv ;

Mancio-Silva, Liliana ;

Romano, Shannon ;

Gorelick, Daniel A. ;

Cohen, David E. ;

Zon, Leonard, I ;

Bhatia, Sangeeta N. ;

North, Trista E. ;

Goessling, Wolfram .

GASTROENTEROLOGY, 2019, 156 (06) :1788-+

[40] IP3-4 kinase Arg1 regulates cell wall homeostasis and surface architecture to promote clearance of Cryptococcus neoformans infection in a mouse model [J].

Li, Cecilia ;

Lev, Sophie ;

Desmarini, Desmarini ;

Kaufman-Francis, Keren ;

Saiardi, Adolfo ;

Silva, Ana P. G. ;

Mackay, Joel P. ;

Thompson, Philip E. ;

Sorrell, Tania C. ;

Djordjevic, Julianne T. .

VIRULENCE, 2017, 8 (08) :1833-1848

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