Regulation of Bone Morphogenetic Protein-4 by Matrix GLA Protein in Vascular Endothelial Cells Involves Activin-like Kinase Receptor 1

Yao, Yucheng; Zebboudj, Amina F.; Shao, E.; Pérez, Martín M.; Boström, Kristina I.

doi:10.1074/jbc.m604239200

Cited by 108 publications

(152 citation statements)

References 43 publications

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“…BMP-2 and BMP-4 have been demonstrated to affect VEGF production via ALK-1/ Smad-1 signaling with concurrent effects on atherogenesis 13,28,43,44) . Despite the fact that there are no data available about statin effects on the BMP/ALK-1/Smad1/VEGF pathway, we did not study the effects of atorvastatin treatment on this signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

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

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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.

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Section: Discussionmentioning

confidence: 99%

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

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“…5,18 For treatment, cells were seeded at a confluence of 50% to 80%, and treatments were added to the media 20-24 hours later. Transient transfections of HAECs with siRNA were performed with Lipofectamine 2000 (Invitrogen) using 60nM siRNA as previously described.…”

Section: Cell Culture and Sirna Transfectionmentioning

confidence: 99%

“…5,10 MGP is induced by BMP-4 in ECs and antagonizes BMP-2, BMP-4, and BMP-7. 2,11 It inhibits angiogenesis through feedback inhibition of BMP-4, 9,12 and lack of MGP results in AVMs similar to ALK1 deficiency.…”

Section: Introductionmentioning

confidence: 99%

Crossveinless 2 regulates bone morphogenetic protein 9 in human and mouse vascular endothelium

Yao

Jumabay

et al. 2012

Blood

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The importance of morphogenetic proteins (BMPs) and their antagonists in vascular development is increasingly being recognized. BMP-4 is essential for angiogenesis and is antagonized by matrix Gla protein (MGP) and crossveinless 2 (CV2), both induced by the activin receptor like-kinase 1 (ALK1) when stimulated by BMP-9. In this study, however, we show that CV2 preferentially binds and inhibits BMP-9 thereby providing strong feedback inhibition for BMP-9/ALK1 signaling rather than for BMP-4/ALK2 signaling. CV2 disrupts complex formation involving ALK2, ALK1, BMP-4, and BMP-9 required for the induction of both BMP antagonists. It also limits VEGF expression, proliferation, and tube formation in ALK1-expressing endothelial cells.

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“…We have previously shown that BMP-4 and -7 induce expression of ALK1 in endothelial cells (ECs) (12,13). In turn, activation of ALK1 by its ligand BMP-9 induces expression of matrix Gla protein (MGP), an inhibitor of BMP-2, -4 and -7 (12)(13)(14)(15), which is highly expressed in brain, lungs, and kidneys (13,16).…”

mentioning

confidence: 99%

“…In turn, activation of ALK1 by its ligand BMP-9 induces expression of matrix Gla protein (MGP), an inhibitor of BMP-2, -4 and -7 (12)(13)(14)(15), which is highly expressed in brain, lungs, and kidneys (13,16). MGP provides negative feedback inhibition for BMP-4 and -7 (13,17), which limits the ALK1 induction.…”

mentioning

confidence: 99%

Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency

Yao¹,

Yao²,

Radparvar³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Cerebral arteriovenous malformations (AVMs) are common vascular abnormalities that may lead to strokes. Signaling by bone morphogenetic proteins (BMPs) and Notch play important roles in the formation of cerebral AVMs, but the cross-talk between the pathways is poorly understood. We report that gene deletion of matrix Gla protein (MGP), a BMP inhibitor, causes cerebral AVMs in mice by activating activin receptor-like kinase 1, a BMP receptor. This activation enhances Notch activity and disrupts endothelial cell differentiation by inducing the Notch ligands Jagged 1 and 2. Reducing Jagged 1 and 2 expression prevents the disruption in differentiation and AVM formation. The findings suggest that MGP maintains the balance between BMP and Notch signaling and promotes a normal brain vasculature.

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Regulation of Bone Morphogenetic Protein-4 by Matrix GLA Protein in Vascular Endothelial Cells Involves Activin-like Kinase Receptor 1

Cited by 108 publications

References 43 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

Crossveinless 2 regulates bone morphogenetic protein 9 in human and mouse vascular endothelium

Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency

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