Limits...
LRP1 regulates architecture of the vascular wall by controlling PDGFRbeta-dependent phosphatidylinositol 3-kinase activation.

Zhou L, Takayama Y, Boucher P, Tallquist MD, Herz J - PLoS ONE (2009)

Bottom Line: In this study, we found disorganized actin in the form of membrane ruffling and enhanced cell migration in LRP1-deficient (LRP1-/-) SMCs.Normal actin organization was restored and spontaneous SMC migration as well as PDGF-BB-induced chemotaxis was dramatically reduced, despite continued overactivation of TGFbeta signaling, as indicated by high levels of nuclear phospho-Smad2.TGFbeta activation alone is not sufficient for the expression of the Marfan-like vascular phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, Texas, United States of America.

ABSTRACT

Background: Low density lipoprotein receptor-related protein 1 (LRP1) protects against atherosclerosis by regulating the activation of platelet-derived growth factor receptor beta (PDGFRbeta) in vascular smooth muscle cells (SMCs). Activated PDGFRbeta 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 (TGFbeta) signaling are present in smooth muscle-specific LRP1 knockout (smLRP1-/-) mice. To investigate the role of LRP1-regulated PI3K activation by PDGFRbeta in atherogenesis, we generated a strain of smLRP1-/- mice in which tyrosine 739/750 of the PDGFRbeta had been mutated to phenylalanines (PDGFRbeta 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 TGFbeta 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 PDGFRbeta-dependent activation of PI3K. TGFbeta activation alone is not sufficient for the expression of the Marfan-like vascular phenotype. Thus, regulation of PI3 Kinase by PDGFRbeta is essential for maintaining vascular integrity, and for the prevention of atherosclerosis as well as Marfan syndrome.

Show MeSH

Related in: MedlinePlus

Reduced atherosclerotic lesions in smLRP1−/−; LDLR−/−; PDGFRβ F2/F2 mutant mice.(A) Unopened (a–c) & Oil Red O stained (d–f) aortas from 10-month old mice of the indicated genotypes. Mice were maintained on standard rodent chow diet. Arrows indicate lipid-laden atherosclerotic lesions. (B) Histological analysis of aortas from 8-month old mice of the indicated genotypes. g–l: HE stain, m–r: trichrome stain, s–x: elastin stain. g,h,i,m,n,o,s,t u: aortic arch; j,k,l,p,q,r,v,w,x: thoracic aorta. Scale bar, 20 µm. (C, D, E, F) Atherosclerotic lesions (C), length (D), thickness (E) and cell number per cm2 (F) of the indicated genotypes were quantified using Image J software (NIH). Results from 3 mice per group are presented as mean±SD. * p<0.05, ** p<0.01, *** p<0.001.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2734324&req=5

pone-0006922-g003: Reduced atherosclerotic lesions in smLRP1−/−; LDLR−/−; PDGFRβ F2/F2 mutant mice.(A) Unopened (a–c) & Oil Red O stained (d–f) aortas from 10-month old mice of the indicated genotypes. Mice were maintained on standard rodent chow diet. Arrows indicate lipid-laden atherosclerotic lesions. (B) Histological analysis of aortas from 8-month old mice of the indicated genotypes. g–l: HE stain, m–r: trichrome stain, s–x: elastin stain. g,h,i,m,n,o,s,t u: aortic arch; j,k,l,p,q,r,v,w,x: thoracic aorta. Scale bar, 20 µm. (C, D, E, F) Atherosclerotic lesions (C), length (D), thickness (E) and cell number per cm2 (F) of the indicated genotypes were quantified using Image J software (NIH). Results from 3 mice per group are presented as mean±SD. * p<0.05, ** p<0.01, *** p<0.001.

Mentions: We found significantly decreased atherosclerotic lesions in the aortic arch and abdominal aorta of smLRP1−/−; LDLR−/−; PDGFRβ F2/F2 mice (Figure 3A, C). H&E, trichrome and elastin staining revealed well-arranged spindle-shaped SMCs, reduced extracellular matrix, and virtually normal elastic layers in smLRP1−/−; LDLR−/−; PDGFRβ F2/F2 aortas (Figure 3B). Vascular wall thickness, hypercellularity and length of the aortas in smLRP1−/−; LDLR−/−; PDGFRβ F2/F2 mutants were markedly reduced to approximately normal levels (Figure 3B, D, E, F). However, the prominent aneurysms of the mesenteric arteries, which are a hallmark of smLRP−/− mice, were notably not abolished in smLRP1−/−; LDLR−/−; PDGFRβ F2/F2 mice (Figure 3A), suggesting that atherogenesis and aneurysm formation employ at least partially different molecular or regionally distinct mechanisms.


LRP1 regulates architecture of the vascular wall by controlling PDGFRbeta-dependent phosphatidylinositol 3-kinase activation.

Zhou L, Takayama Y, Boucher P, Tallquist MD, Herz J - PLoS ONE (2009)

Reduced atherosclerotic lesions in smLRP1−/−; LDLR−/−; PDGFRβ F2/F2 mutant mice.(A) Unopened (a–c) & Oil Red O stained (d–f) aortas from 10-month old mice of the indicated genotypes. Mice were maintained on standard rodent chow diet. Arrows indicate lipid-laden atherosclerotic lesions. (B) Histological analysis of aortas from 8-month old mice of the indicated genotypes. g–l: HE stain, m–r: trichrome stain, s–x: elastin stain. g,h,i,m,n,o,s,t u: aortic arch; j,k,l,p,q,r,v,w,x: thoracic aorta. Scale bar, 20 µm. (C, D, E, F) Atherosclerotic lesions (C), length (D), thickness (E) and cell number per cm2 (F) of the indicated genotypes were quantified using Image J software (NIH). Results from 3 mice per group are presented as mean±SD. * p<0.05, ** p<0.01, *** p<0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2734324&req=5

pone-0006922-g003: Reduced atherosclerotic lesions in smLRP1−/−; LDLR−/−; PDGFRβ F2/F2 mutant mice.(A) Unopened (a–c) & Oil Red O stained (d–f) aortas from 10-month old mice of the indicated genotypes. Mice were maintained on standard rodent chow diet. Arrows indicate lipid-laden atherosclerotic lesions. (B) Histological analysis of aortas from 8-month old mice of the indicated genotypes. g–l: HE stain, m–r: trichrome stain, s–x: elastin stain. g,h,i,m,n,o,s,t u: aortic arch; j,k,l,p,q,r,v,w,x: thoracic aorta. Scale bar, 20 µm. (C, D, E, F) Atherosclerotic lesions (C), length (D), thickness (E) and cell number per cm2 (F) of the indicated genotypes were quantified using Image J software (NIH). Results from 3 mice per group are presented as mean±SD. * p<0.05, ** p<0.01, *** p<0.001.
Mentions: We found significantly decreased atherosclerotic lesions in the aortic arch and abdominal aorta of smLRP1−/−; LDLR−/−; PDGFRβ F2/F2 mice (Figure 3A, C). H&E, trichrome and elastin staining revealed well-arranged spindle-shaped SMCs, reduced extracellular matrix, and virtually normal elastic layers in smLRP1−/−; LDLR−/−; PDGFRβ F2/F2 aortas (Figure 3B). Vascular wall thickness, hypercellularity and length of the aortas in smLRP1−/−; LDLR−/−; PDGFRβ F2/F2 mutants were markedly reduced to approximately normal levels (Figure 3B, D, E, F). However, the prominent aneurysms of the mesenteric arteries, which are a hallmark of smLRP−/− mice, were notably not abolished in smLRP1−/−; LDLR−/−; PDGFRβ F2/F2 mice (Figure 3A), suggesting that atherogenesis and aneurysm formation employ at least partially different molecular or regionally distinct mechanisms.

Bottom Line: In this study, we found disorganized actin in the form of membrane ruffling and enhanced cell migration in LRP1-deficient (LRP1-/-) SMCs.Normal actin organization was restored and spontaneous SMC migration as well as PDGF-BB-induced chemotaxis was dramatically reduced, despite continued overactivation of TGFbeta signaling, as indicated by high levels of nuclear phospho-Smad2.TGFbeta activation alone is not sufficient for the expression of the Marfan-like vascular phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, Texas, United States of America.

ABSTRACT

Background: Low density lipoprotein receptor-related protein 1 (LRP1) protects against atherosclerosis by regulating the activation of platelet-derived growth factor receptor beta (PDGFRbeta) in vascular smooth muscle cells (SMCs). Activated PDGFRbeta 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 (TGFbeta) signaling are present in smooth muscle-specific LRP1 knockout (smLRP1-/-) mice. To investigate the role of LRP1-regulated PI3K activation by PDGFRbeta in atherogenesis, we generated a strain of smLRP1-/- mice in which tyrosine 739/750 of the PDGFRbeta had been mutated to phenylalanines (PDGFRbeta 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 TGFbeta 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 PDGFRbeta-dependent activation of PI3K. TGFbeta activation alone is not sufficient for the expression of the Marfan-like vascular phenotype. Thus, regulation of PI3 Kinase by PDGFRbeta is essential for maintaining vascular integrity, and for the prevention of atherosclerosis as well as Marfan syndrome.

Show MeSH
Related in: MedlinePlus