TY - JOUR
T1 - LRP1 regulates architecture of the vascular wall by controlling PDGFRβ-dependent phosphatidylinositol 3-kinase activation
AU - Zhou, Li
AU - Takayama, Yoshiharu
AU - Boucher, Philippe
AU - Tallquist, Michelle D.
AU - Herz, Joachim
PY - 2009/9/9
Y1 - 2009/9/9
N2 - Background: Low density lipoprotein receptor-related protein 1 (LRP1) protects against atherosclerosis by regulating the activation of platelet-derived growth factor receptor β (PDGFRβ) in vascular smooth muscle cells (SMCs). Activated PDGFRβ 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 β (TGFβ) signaling are present in smooth muscle-specific LRP1 knockout (smLRP1-/-) mice. To investigate the role of LRP1-regulated PI3K activation by PDGFRβ in atherogenesis, we generated a strain of smLRP1-/- mice in which tyrosine 739/750 of the PDGFRβ had been mutated to phenylalanines (PDGFRb 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 TGFβ 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 PDGFRβ-dependent activation of PI3K. TGFβ activation alone is not sufficient for the expression of the Marfan-like vascular phenotype. Thus, regulation of PI3 Kinase by PDGFRβ is essential for maintaining vascular integrity, and for the prevention of atherosclerosis as well as Marfan syndrome.
AB - Background: Low density lipoprotein receptor-related protein 1 (LRP1) protects against atherosclerosis by regulating the activation of platelet-derived growth factor receptor β (PDGFRβ) in vascular smooth muscle cells (SMCs). Activated PDGFRβ 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 β (TGFβ) signaling are present in smooth muscle-specific LRP1 knockout (smLRP1-/-) mice. To investigate the role of LRP1-regulated PI3K activation by PDGFRβ in atherogenesis, we generated a strain of smLRP1-/- mice in which tyrosine 739/750 of the PDGFRβ had been mutated to phenylalanines (PDGFRb 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 TGFβ 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 PDGFRβ-dependent activation of PI3K. TGFβ activation alone is not sufficient for the expression of the Marfan-like vascular phenotype. Thus, regulation of PI3 Kinase by PDGFRβ is essential for maintaining vascular integrity, and for the prevention of atherosclerosis as well as Marfan syndrome.
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U2 - 10.1371/journal.pone.0006922
DO - 10.1371/journal.pone.0006922
M3 - Article
C2 - 19742316
AN - SCOPUS:70349093134
SN - 1932-6203
VL - 4
JO - PloS one
JF - PloS one
IS - 9
M1 - e6922
ER -