Endoglin Has a Crucial Role in Blood Cell–Mediated Vascular Repair

Laake, Linda W. van; Driesche, Sander van den; Post, Simone; Feijen, A.; Jansen, Maurits A.; Driessens, M. H. E.; Mager, Johannes J.; Snijder, Repke J.; Westermann, C. J. J.; Doevendans, Pieter A.; Echteld, C.J.A. van; Dijke, Peter ten; Arthur, Helen M.; Goumans, Marie–José; Lebrin, Franck; Mummery, Christine L.

doi:10.1161/circulationaha.106.639161

Cited by 131 publications

(120 citation statements)

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“…In addition, endoglin affects the efficiency of formation of the hemangioblast, a common embryonic progenitor of the hematopoietic and endothelial lineages [Perlingeiro, 2007]. Finally, supporting the relevance of endoglinexpressing circulating precursors, it was reported that endoglin has a crucial role in blood mononuclear cell-mediated vascular repair [van Laake et al, 2006]. Together, these studies support the hypothesis that endoglin expression is required for multiple cell precursors to begin tissue formation, respond to injury, and suggest that age-dependent loss of endoglin underlies an impaired response to vascular injury.…”

Section: Endoglin and Vascular Smooth Muscle Cell Developmentmentioning

confidence: 87%

Novel biochemical pathways of endoglin in vascular cell physiology

Bernabeu

Conley

Vary

2007

J of Cellular Biochemistry

119

123

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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.

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Section: Endoglin and Vascular Smooth Muscle Cell Developmentmentioning

confidence: 87%

Novel biochemical pathways of endoglin in vascular cell physiology

Bernabeu

Conley

Vary

2007

J of Cellular Biochemistry

119

123

View full text Add to dashboard Cite

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“…It is strongly expressed in endothelial cells and smooth muscle cells of blood vessels in various pathological situations, including cancer, angiogenesis and atherosclerosis [4][5][6][7][8] . It is also present on monocytes and is upregulated during monocyte-macrophage transition, playing a crucial role in monocyte-mediated vascular repair 9) . Endoglin is able to modulate the activity of different TGF-receptors, ALK-1 and ALK-5, in order to affect TGF-signaling 10) .…”

Section: Introductionmentioning

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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“…Anemia observed in patients with HHT1 and in Endoglin -/-mice is another indicator for a possible role of Endoglin in erythropoiesis. In the adult setting, in addition to its involvement in angiogenesis and vascular repair (Hayrabedyan et al, 2005;van Laake et al, 2006), Endoglin is expressed in long-term repopulating hematopoietic stem cells from bone marrow (Chen et al, 2002) and was reported to play a role in erythroid lineage differentiation (Moody et al, 2007). Increased levels of Endoglin expression were also found in tumors (Fonsatti et al, 2001), atherosclerotic plaques (Conley et al, 2000) and during inflammation and wound healing (Torsney et al, 2002).…”

Section: Introductionmentioning

confidence: 99%