Endoglin increases eNOS expression by modulating Smad2 protein levels and Smad2‐dependent TGF‐β signaling

Santibáñez, Juan F.; Letamendı́a, Ainhoa; Pérez‐Barriocanal, Fernando; Silvestri, Cristoforo; Saura, Marta; Vary, Calvin P.H.; López‐Novoa, José M.; Attisano, Liliana; Bernabéu, Carmelo

doi:10.1002/jcp.20878

Cited by 103 publications

(88 citation statements)

References 66 publications

(115 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Endoglin expression has been demonstrated in human 8,16) , porcine 32) and mouse atherosclerotic vessels 4) . Moreover, several in vitro studies have demonstrated the crucial role of endoglin in 33) and activation of the ALK-5/Smad-2 pathway 20) . In this study, we demonstrate for the first time the concurrent increased expression of both endoglinrelated pathways, including ALK-5/pSmad-2 and ALK-1/pSmad-1, in atherogenesis and with respect to the non-lipid-lowering effects of atorvastatin.…”

Section: Discussionmentioning

confidence: 99%

“…Many in vitro studies demonstrated that endoglin affects TGF-signaling by modulation of ALKs and Smads activity 20,21) . In general, recent studies have revealed complicated interplay between two signaling pathways and endoglin.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the endoglin/ALK-5/Smad2/3 pathway leads to the inhibition of endothelial cells and quiescence of the endothelium 1,11) . The roles of TGF-1, endoglin, ALK-1, ALK-5 and various Smads in atherosclerosis have been partially studied within the past decade in vivo in animals 14,15) , humans [16][17][18] and in vitro [19][20][21] , suggesting their participation in atherogenesis. Despite this, the precise role of endoglin and its activated signaling pathway in atherogenesis is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Activation of TGF-β Receptors and Smad Proteins by Atorvastatin is Related to Reduced Atherogenesis in ApoE/LDLR Double Knockout Mice

Vecerova¹,

Strasky²,

Rathouska³

et al. 2012

JAT

View full text Add to dashboard Cite

Aim: Transforming growth factor-beta (TGF-) plays important role in atherogenesis via TGF-receptors and Smad proteins, which determine its signaling activity. In this study, we hypothesized, whether non-lipid related effects of atorvastatin, affect both endoglin/ALK-5/Smad2/eNOS and/or endoglin/ALK-1/Smad1/VEGF previously proposed pathways in ApoE/LDLR double knockout mice. Methods: ApoE/LDLR double knockout mice were divided into two groups. The chow group (CHOW) (n 8) was fed with chow diet, while in the atorvastatin group (ATV) (n 8) atorvastatin was added to the chow diet at dose 50 mg/kg/day. Biochemical analyses of lipid profile, lesion area measurement, immunohistochemistry and Western blot analysis of endoglin, ALK-1, 5, phosphorylated and non-phosphorylated forms Smad-1, 2, VEGF and eNOS proteins in mice aorta were performed. Results: Biochemical analysis of blood serum and morphometric analysis of aortic lesion size showed that atorvastatin treatment resulted in a significant increase of cholesterol levels and simultaneously in reduced lesion size in aortic sinus when compared to CHOW mice. Western blot analysis revealed that atorvastatin treatment significantly increase the expressions of endoglin by 102%, ALK-1 by 113%, ALK-5 by 296%, pSmad-1 by 202%, pSmad-2 by 34%, VEGF by 68% and eNOS by 687% as compared with CHOW mice. Immunofluorescence staining revealed endoglin coexpression with all studied markers that were increased by atorvastatin treatment mainly in endothelial cells covering atherosclerotic plaques. Conclusion: This study shows that atorvastatin treatment increases the expression of endoglin, ALK-1, ALK-5, phosphorylated forms of Smad1 and Smad2, VEGF and eNOS and reduces atherosclerotic lesion size beyond its lipid lowering effects. Therefore, we propose that endoglin related receptors and signal transducers might play protective role in atherogenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Activation of TGF-β Receptors and Smad Proteins by Atorvastatin is Related to Reduced Atherogenesis in ApoE/LDLR Double Knockout Mice

Vecerova¹,

Strasky²,

Rathouska³

et al. 2012

JAT

View full text Add to dashboard Cite

show abstract

“…Thus, although endoglin shows an inhibitory effect on TGFβ/ALK5/Smad3 cellular responses Guo et al, 2004;Lebrin et al, 2004;Blanco et al, 2005;Scherner et al, 2007], it enhances ALK5/ Smad2 signaling Carvalho et al, 2004;Santibanez et al, 2007]. In addition, endoglin may be required for TGFβ1/ALK1 signaling in some cell types, especially endothelial cells.…”

Section: Role Of Endoglin In the Modulation Of Tgfβ-dependent Cell Rementioning

confidence: 99%

Novel biochemical pathways of endoglin in vascular cell physiology

Bernabeu

Conley

Vary

2007

J of Cellular Biochemistry

Self Cite

119

123

View full text Add to dashboard Cite

The broad role of the transforming growth factor beta (TGFβ) signaling pathway in vascular development, homeostasis, and repair is well appreciated. Endoglin is emerging as a novel, complex, and poorly understood regulatory component of the TGFβ receptor complex, whose importance is underscored by its recognition as the site of mutations causing hereditary hemorrhagic telangiectasia (HHT) [McAllister et al., 1994]. Extensive analyses of endoglin function in normal developmental mouse models [Bourdeau et al., 1999;Li et al., 1999;Arthur et al., 2000] and in HHT animal models [Bourdeau et al., 2000;Torsney et al., 2003] exemplify the importance of understanding endoglin's biochemical functions. However, novel mechanisms underlying the regulation of these pathways continue to emerge. These mechanisms include modification of TGFβ receptor signaling at the ligand and receptor activation level, direct effects of endoglin on cell adhesion and migration, and emerging roles for endoglin in the determination of stem cell fate and tissue patterning. The purpose of this review is to highlight the cellular and molecular studies that underscore the central role of endoglin in vascular development and disease. Keywords endoglin; transforming growth factor-beta receptors; hereditary hemorrhagic telangiectasia; vascular pathology; vascular endothelium; vascular smooth muscle The canonical transforming growth factor beta (TGFβ) signaling pathway comprises seven type I and five type II TGFβ receptors [Manning etal.,2002]. The TGFβ type I receptors are serine and threonine kinases, which include activin-like kinase 1 (ALK1) and TβRI, also known as ALK5. ALK1 and ALK5 associate with, and are activated via ligand-dependent phosphorylation [Vivien and Wrana, 1995] by the type II TGFβ receptor, TβRII [Wrana et al., 1992]. The activated type I receptor propagates canonical or Smad-dependent signals by phosphorylating Smad proteins [Shi and Massague, 2003;Feng and Derynck, 2005]. Another component of the TGFβ system is endoglin. Endoglin is a transmembrane protein [Gougos and Letarte, 1990] that acts as an auxiliary receptor for TGFβ [Cheifetz et al., 1992;Barbara et al., 1999]. Of note, mutations in endoglin (ENG) [McAllister et al., 1994] and ALK1 [Johnson et al., 1996] genes cause the vascular dysplasia hereditary hemorrhagic telangiectasia (HHT), termed HHT1 and HHT2, respectively.

show abstract

“…33,34 Interestingly, endoglin modulates endothelial NO synthase (eNOS) expression and activity, thus affecting vascular tone. [35][36][37] In the present study, we hypothesized that lower concentrations of relevant markers of NO formation (plasma and whole blood nitrite) would be found in hypertensive disorders of pregnancy compared with those found in healthy pregnancies. In addition, given the fact that sFLT-1 and sEng interfere with eNOS activity, we hypothesized that inverse relationships exist between the circulating concentrations of markers of NO formation and sFLT-1 or sEng during pregnancy.…”

mentioning

confidence: 92%

Nitric Oxide Formation Is Inversely Related to Serum Levels of Antiangiogenic Factors Soluble Fms-Like Tyrosine Kinase-1 and Soluble Endogline in Preeclampsia

et al. 2008

View full text Add to dashboard Cite

Abstract-Deficient NO formation has been implicated in hypertensive disorders of pregnancy. However, no previous study has compared the circulating nitrite concentrations in healthy pregnant women with those found in hypertensive disorders of pregnancy. Moreover, 2 antiangiogenic factors produced in the placenta (soluble fms-like tyrosine kinase-1 and soluble endogline) may affect NO formation during pregnancy. Here, we hypothesized that lower concentrations of markers of NO formation exist in hypertensive disorders of pregnancy and that inverse relationships exist between these markers and soluble fms-like tyrosine kinase-1 or soluble endogline. In this cross-sectional study, we compared 58 healthy pregnant women with 56 gestational hypertensive subjects and 45 preeclamptic patients. We measured plasma and whole blood nitrite concentrations using an ozone-based chemiluminescence assay and serum soluble fms-like tyrosine kinase-1 and soluble endogline concentrations using enzyme immunoassays. Whole blood nitrite levels were significantly lower in gestational hypertensive subjects and preeclamptic patients (Ϫ36% and Ϫ58%, respectively; both PϽ0.05) compared with healthy pregnant women. The plasma nitrite levels were Ϸ37% lower in both groups with hypertensive disorders of pregnancy compared with the group with normotensive pregnancies (both PϽ0.05). As expected, we found higher circulating soluble fms-like tyrosine kinase-1 and soluble endogline concentrations in preeclampsia compared with gestational hypertensive subjects or with healthy pregnancies (both PϽ0.05). Key Words: NO Ⅲ nitrite Ⅲ whole blood nitrite Ⅲ preeclampsia Ⅲ sEng Ⅲ sFLT-1 N ormal human pregnancy is accompanied by increased blood volume that is accommodated within the cardiovascular system by systemic vasodilatation. 1 This vasodilatation involves increased NO formation, thus decreasing peripheral vascular resistance in healthy pregnant women. 2,3 On the other hand, deficient NO formation has been implicated in hypertensive disorders of pregnancy, such as preeclampsia and gestational hypertension. 4 -7 Indeed, previous studies compared the circulating concentrations of NO metabolites (nitriteϩnitrate) in the plasma from preeclamptic women with those found in healthy pregnant women. 8 -13 Conflicting results were reported, and some studies showed higher, 14 similar, 10,12 or lower 8 nitriteϩnitrate levels in preeclamptic women compared with healthy pregnant women. A possible explanation for these discrepancies is that nitriteϩnitrate may not accurately reflect endogenous NO formation in vivo, and there is mounting evidence that measuring the circulating concentrations of nitrite is an improved alternative to assess endogenously produced NO. [15][16][17][18][19] However, no previous study has compared the circulating nitrite concentrations in healthy pregnant women with those found in women with preeclampsia.The pathophysiology of preeclampsia is not completely known. However, there is evidence that a failure of cytotrophoblast invasion and abse...

show abstract

Endoglin increases eNOS expression by modulating Smad2 protein levels and Smad2‐dependent TGF‐β signaling

Cited by 103 publications

References 66 publications

Activation of TGF-β Receptors and Smad Proteins by Atorvastatin is Related to Reduced Atherogenesis in ApoE/LDLR Double Knockout Mice

Activation of TGF-β Receptors and Smad Proteins by Atorvastatin is Related to Reduced Atherogenesis in ApoE/LDLR Double Knockout Mice

Novel biochemical pathways of endoglin in vascular cell physiology

Nitric Oxide Formation Is Inversely Related to Serum Levels of Antiangiogenic Factors Soluble Fms-Like Tyrosine Kinase-1 and Soluble Endogline in Preeclampsia

Contact Info

Product

Resources

About