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Carmelo Bernabéu - One of the best experts on this subject based on the ideXlab platform.
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Lumican is down-regulated in cells expressing Endoglin. Evidence for an inverse correlationship between Endoglin and Lumican expression.
Matrix Biology, 2020Co-Authors: Luisa-maria Botella, Carmen Langa, Tilman Sánchez-elsner, Calvin P. H. Vary, Jose Ramón Ramirez, Francisco Sanz-rodríguez, Peter J. Roughley, Carmelo BernabéuAbstract:Abstract Endoglin (CD105) is a homodimeric membrane glycoprotein, which acts as a TGF-β coreceptor in the vasculature and plays an important role in cardiovascular development and vascular remodelling. To isolate putative genes regulated by Endoglin expression, a PCR-based RNA fingerprinting technique was carried out. Myoblasts stably transfected with Endoglin showed a decrease in the expression of lumican both at the RNA and protein levels. Lumican is a proteoglycan of the extracellular matrix, belonging to the SLRP (Small Leucine-Rich Repeat Proteoglycans) family. Lumican down-regulation by Endoglin appeared to be controlled, at least in part, at the transcriptional level, as indicated by RT-PCR, and transient transfection experiments using a lumican promoter reporter based vector. This inverse correlation between Endoglin and lumican expression was substantiated by immunohistochemical staining of vessels from human tissues. Thus, cells belonging to the high endothelia, such as tonsil, express a large amount of Endoglin, and the lumican content of their matrix is considerably reduced. Conversely, in resting endothelia, such as that of large vessels, the expression of Endoglin is reduced whereas the amount of lumican is greatly increased. The inverse regulation in the expression of Endoglin and lumican was also evident after TGF-β treatments since Endoglin was up-regulated, whereas lumican was down-regulated by this cytokine. This report describes for the first time a relationship between Endoglin and lumican expression.
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The role of Endoglin in post-ischemic revascularization
Angiogenesis, 2017Co-Authors: Elena Núñez-gómez, Miguel Pericacho, Carmelo Bernabéu, Claudia Ollauri-ibáñez, José M. López-novoaAbstract:Following arterial occlusion, blood vessels respond by forming a new network of functional capillaries (angiogenesis), by reorganizing preexisting capillaries through the recruitment of smooth muscle cells to generate new arteries (arteriogenesis) and by growing and remodeling preexisting collateral arterioles into physiologically relevant arteries (collateral development). All these processes result in the recovery of organ perfusion. The importance of Endoglin in post-occlusion reperfusion is sustained by several observations: (1) Endoglin expression is increased in vessels showing active angiogenesis/remodeling; (2) genetic Endoglin haploinsufficiency in humans causes deficient angiogenesis; and (3) the reduction of Endoglin expression by gene disruption or the administration of Endoglin-neutralizing antibodies reduces angiogenesis and revascularization. However, the precise role of Endoglin in the several processes associated with revascularization has not been completely elucidated and, in some cases, the function ascribed to Endoglin by different authors is controversial. The purpose of this review is to organize in a critical way the information available for the role of Endoglin in several phenomena (angiogenesis, arteriogenesis and collateral development) associated with post-ischemic revascularization.
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Expression of Endoglin isoforms in the myeloid lineage and their role during aging and macrophage polarization
Journal of Cell Science, 2014Co-Authors: Mikel Aristorena, Luisa-maria Botella, Francisco J. Blanco, M. De Las Casas-engel, Luisa Ojeda-fernandez, Eunate Gallardo-vara, Angel L. Corbí, Carmelo BernabéuAbstract:Endoglin plays a crucial role in pathophysiological processes such as hereditary hemorrhagic telangiectasia (HHT), preeclampsia and cancer. Endoglin expression is upregulated during the monocyte-to-macrophage transition, but little is known about its regulation and function in these immune cells. Two different alternatively spliced isoforms of Endoglin have been reported, L-Endoglin and S-Endoglin. Although L-Endoglin is the predominant variant, here, we found that there was an increased expression of the S-Endoglin isoform during senescence of the myeloid lineage in human and murine models. We performed a stable isotope labelling of amino acids in cell culture (SILAC) analysis of both L-Endoglin and S-Endoglin transfectants in the human promonocytic cell line U937. Analysis of differentially expressed protein clusters allowed the identification of cellular activities affected during aging. S-Endoglin expression led to decreased cellular proliferation and a decreased survival response to granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced apoptosis, as well as increased oxidative stress. Gene expression and functional studies suggested that there was a non-redundant role for each Endoglin isoform in monocyte biology. In addition, we found that S-Endoglin impairs the monocytic differentiation into the pro-inflammatory M1 phenotype and contributes to the compromised status of macrophage functions during aging.
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endothelial Endoglin is involved in inflammation role in leukocyte adhesion and transmigration
Blood, 2013Co-Authors: Elisa Rossi, Carmen Langa, Luisa-maria Botella, Carlos Cabañas, Francisco J. Blanco, Francisco Sanzrodriguez, Nelida Eleno, Annette Duwell, Jose M Lopeznovoa, Carmelo BernabéuAbstract:Human Endoglin is an RGD-containing transmembrane glycoprotein identified in vascular endothelial cells. Although Endoglin is essential for angiogenesis and its expression is upregulated in inflammation and at sites of leukocyte extravasation, its role in leukocyte trafficking is unknown. This function was tested in Endoglin heterozygous mice ( Eng +/- ) and their wild type siblings Eng +/+ treated with carrageenan or LPS as inflammatory agents. Both stimuli showed that inflammation-induced leukocyte trans-endothelial migration to peritoneum or lungs was significantly lower in Eng +/- than in Eng +/+ mice. Leukocyte transmigration through cell monolayers of Endoglin transfectants was clearly enhanced in the presence of Endoglin. Coating transwells with the RGD-containing extracellular domain of Endoglin, enhanced leukocyte transmigration, and this increased motility was inhibited by soluble Endoglin. Leukocytes stimulated with CXCL12, a chemokine involved in inflammation, strongly adhered to Endoglin-coated plates and to Endoglin-expressing endothelial cells. This Endoglin-dependent adhesion was abolished by soluble Endoglin, RGD peptides, the anti-integrin α5β1 inhibitory antibody LIA1/2 and the chemokine receptor inhibitor AMD3100. These results demonstrate for the first time that endothelial Endoglin interacts with leukocyte integrin α5β1 via its RGD motif, and this adhesion process is stimulated by the inflammatory chemokine CXCL12, suggesting a regulatory role for Endoglin in transendothelial leukocyte trafficking.
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Endoglin Upregulation in the Liver after Bile Duct Ligation in Rats
The Open Gastroenterology Journal, 2011Co-Authors: Fernando Pérez-barriocanal, Carmelo Bernabéu, Maria Angeles Arevalo, Neil G. Docherty, Annette Düwel, Juan V. Rivas-elena, José Manuel González-buitrago, Alejandro Esteller, José M. López-novoaAbstract:Background: Transforming growth factor beta 1 (TGF- 1) has been implicated in the stimulation of extracellu- lar matrix synthesis in acute and chronic liver disease. Endoglin (CD-105) is a membrane glycoprotein that binds TGF- 1 with high affinity. Endoglin is overexpressed in several model of fibrosis. The goal of the present study was to evaluate the effect of bile duct ligation (BDL) on Endoglin expression and the effect of Endoglin overexpression on liver fibrosis in rats. Methods: Rat livers were transfected with a vector containing full length human Endoglin (h-end) or an empty vector (mock) and 48 hours after were subjected to either BDL or sham operation (SO). Eighteen days after, a blood sample was obtained and bilirubin and serum enzyme activities were measured to assess liver damage. Liver fibrosis was quantified by a computer-assisted image analysis of Sirius red stained livers and by liver hydroxyproline content. Endoglin expres- sion in the liver tissue was assessed by Western blot and immunohystochemistry. Results: Both immunohistochemistry and Western blot reveals Endoglin upregulation after BDL in rats. In addition, these techniques also reveal effective human Endoglin transfection in the rat's liver. After BDL, liver fibrosis and plasma levels of enzymes were similar in h-end transfected and mock-transfected rats. Western blots showed higher Endoglin expression after BDL in h-end transfected and mock-transfected rats. Conclusions: The present study provides clear evidence that Endoglin is upregulated in the liver of rats with BDL. h-end overexpression did not improve liver fibrosis after BDL in rats.
Calvin P. H. Vary - One of the best experts on this subject based on the ideXlab platform.
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Lumican is down-regulated in cells expressing Endoglin. Evidence for an inverse correlationship between Endoglin and Lumican expression.
Matrix Biology, 2020Co-Authors: Luisa-maria Botella, Carmen Langa, Tilman Sánchez-elsner, Calvin P. H. Vary, Jose Ramón Ramirez, Francisco Sanz-rodríguez, Peter J. Roughley, Carmelo BernabéuAbstract:Abstract Endoglin (CD105) is a homodimeric membrane glycoprotein, which acts as a TGF-β coreceptor in the vasculature and plays an important role in cardiovascular development and vascular remodelling. To isolate putative genes regulated by Endoglin expression, a PCR-based RNA fingerprinting technique was carried out. Myoblasts stably transfected with Endoglin showed a decrease in the expression of lumican both at the RNA and protein levels. Lumican is a proteoglycan of the extracellular matrix, belonging to the SLRP (Small Leucine-Rich Repeat Proteoglycans) family. Lumican down-regulation by Endoglin appeared to be controlled, at least in part, at the transcriptional level, as indicated by RT-PCR, and transient transfection experiments using a lumican promoter reporter based vector. This inverse correlation between Endoglin and lumican expression was substantiated by immunohistochemical staining of vessels from human tissues. Thus, cells belonging to the high endothelia, such as tonsil, express a large amount of Endoglin, and the lumican content of their matrix is considerably reduced. Conversely, in resting endothelia, such as that of large vessels, the expression of Endoglin is reduced whereas the amount of lumican is greatly increased. The inverse regulation in the expression of Endoglin and lumican was also evident after TGF-β treatments since Endoglin was up-regulated, whereas lumican was down-regulated by this cytokine. This report describes for the first time a relationship between Endoglin and lumican expression.
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Endoglin Regulates Cancer–Stromal Cell Interactions in Prostate Tumors
Cancer Research, 2011Co-Authors: Diana Romero, Aleksandra Terzic, Barbara A. Conley, Raymond C. Bergan, Liangru Contois, Kira Young, Christine F. O'neill, Peter C. Brooks, Calvin P. H. VaryAbstract:Endoglin is an accessory receptor for TGF-β that has been implicated in prostate cancer cell detachment, migration, and invasiveness. However, the pathophysiologic significance of Endoglin with respect to prostate tumorigenesis has yet to be fully established. In this study, we addressed this question by investigation of Endoglin-dependent prostate cancer progression in a TRAMP (transgenic adenocarcinoma mouse prostate) mouse model where Endoglin was genetically deleted. In this model, Endoglin was haploinsufficient such that its allelic deletion slightly increased the frequency of tumorigenesis, yet produced smaller, less vascularized, and less metastatic tumors than TRAMP control tumors. Most strikingly, TRAMP: eng +/− -derived tumors lacked the pronounced infiltration of carcinoma-associated fibroblasts (CAF) that characterize TRAMP prostate tumors. Studies in human primary prostate-derived stromal cells (PrSC) confirmed that suppressing Endoglin expression decreased cell proliferation, the ability to recruit endothelial cells, and the ability to migrate in response to tumor cell–conditioned medium. We found increased levels of secreted insulin-like growth factor–binding proteins (IGFBP) in the conditioned medium from Endoglin-deficient PrSCs and that Endoglin-dependent regulation of IGFBP-4 secretion was crucial for stromal cell–conditioned media to stimulate prostate tumor cell growth. Together, our results firmly establish the pathophysiologic involvement of Endoglin in prostate cancer progression; furthermore, they show how Endoglin acts to support the viability of tumor-infiltrating CAFs in the tumor microenvironment to promote neovascularization and growth. Cancer Res; 71(10); 3482–93. ©2011 AACR .
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Endoglin suppresses human prostate cancer metastasis
Clinical & Experimental Metastasis, 2011Co-Authors: Diana Romero, Clarissa S. Craft, Borko Jovanovic, Minalini Lakshman, Xiaoke Huang, Vijayalakshmi Ananthanarayanan, Calvin P. H. VaryAbstract:Endoglin is a transmembrane receptor that suppresses human prostate cancer (PCa) cell invasion. Small molecule therapeutics now being tested in humans can activate Endoglin signaling. It is not known whether Endoglin can regulate metastatic behavior, PCa tumor growth, nor what signaling pathways are linked to these processes. This study sought to investigate the effect of Endoglin on these parameters. We used a murine orthotopic model of human PCa metastasis, designed by us to measure effects at early steps in the metastatic cascade, and implanted PCa cells stably engineered to express differing levels of Endoglin. We now extend this model to measure cancer cells circulating in the blood. Progressive Endoglin loss led to progressive increases in the number of circulating PCa cells as well as to the formation of soft tissue metastases. Endoglin was known to suppress invasion by activating the Smad1 transcription factor. We now show that it selectively activates specific Smad1-responsive genes, including JUNB, STAT1, and SOX4. Increased tumor growth and increased Ki67 expression in tissue was seen only with complete Endoglin loss. By showing that Endoglin increased TGFβ-mediated suppression of cell growth in vitro and TGFβ-mediated signaling in tumor tissue, loss of this growth-suppressive pathway appears to be implicated at least in part for the increased size of Endoglin-deficient tumors. Endoglin is shown for the first time to suppress cell movement out of primary tumor as well as the formation of distant metastasis. It is also shown to co-regulate tumor growth and metastatic behavior in human PCa.
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Endoglin phosphorylation by ALK2 contributes to the regulation of prostate cancer cell migration.
Carcinogenesis, 2009Co-Authors: Diana Romero, Aleksandra Terzic, Barbara A. Conley, Clarissa S. Craft, Borko Jovanovic, Raymond C. Bergan, Calvin P. H. VaryAbstract:Endoglin, a transmembrane glycoprotein that acts as a transforming growth factor-β (TGF-β) coreceptor, is downregulated in PC3-M metastatic prostate cancer cells. When restored, Endoglin expression in PC3-M cells inhibits cell migration in vitro and attenuates the tumorigenicity of PC3-M cells in SCID mice, though the mechanism of Endoglin regulation of migration in prostate cancer cells is not known. The current study indicates that Endoglin is phosphorylated on cytosolic domain threonine residues by the TGF-β type I receptors ALK2 and ALK5 in prostate cancer cells. Importantly, in the presence of constitutively active ALK2, Endoglin did not inhibit cell migration, suggesting that Endoglin phosphorylation regulated PC3-M cell migration. Therefore, our results suggest that Endoglin phosphorylation is a mechanism with relevant functional consequences in prostate cancer cells. These data demonstrate for the first time that TGF-β receptor-mediated phosphorylation of Endoglin is a Smad-independent mechanism involved in the regulation of prostate cancer cell migration.
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Endoglin plays distinct roles in vascular smooth muscle cell recruitment and regulation of arteriovenous identity during angiogenesis
Developmental Dynamics, 2009Co-Authors: Maria L. Mancini, Aleksandra Terzic, Barbara A. Conley, Leif H. Oxburgh, Teodora Nicola, Calvin P. H. VaryAbstract:Blood vessel formation is a multi-step process. Endoglin is a TGFbeta coreceptor required for angiogenesis. Endoglin null embryos exhibit a loss of arteriovenous identity and defective vascular smooth muscle cell (vSMC) recruitment. Haploinsufficiency of Endoglin results in Hereditary Hemorrhagic Telangiectasia (HHT), characterized by a loss of arteriovenous identity and aberrant vSMC incorporation in fragile vessels. We explored a cell-autonomous role for Endoglin in endothelial and vSMCs during angiogenesis by conditionally activating Endoglin expression in wild type or Endoglin null embryos using either smooth muscle (SM22alphacre) or endothelial cell (Tie2cre) promoters to partially rescue vSMC recruitment to the dorsal aorta. Examination of Endoglin null embryos revealed ectopic arterial expression of the venous-specific marker COUPTFII. Endoglin re-expression in endothelial cells restored normal COUPTFII expression. These results suggested that Endoglin plays distinct and cell-autonomous roles in vSMC recruitment and arteriovenous specification via COUPTFII in angiogenesis that may contribute to HHT.
Carmen Langa - One of the best experts on this subject based on the ideXlab platform.
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Lumican is down-regulated in cells expressing Endoglin. Evidence for an inverse correlationship between Endoglin and Lumican expression.
Matrix Biology, 2020Co-Authors: Luisa-maria Botella, Carmen Langa, Tilman Sánchez-elsner, Calvin P. H. Vary, Jose Ramón Ramirez, Francisco Sanz-rodríguez, Peter J. Roughley, Carmelo BernabéuAbstract:Abstract Endoglin (CD105) is a homodimeric membrane glycoprotein, which acts as a TGF-β coreceptor in the vasculature and plays an important role in cardiovascular development and vascular remodelling. To isolate putative genes regulated by Endoglin expression, a PCR-based RNA fingerprinting technique was carried out. Myoblasts stably transfected with Endoglin showed a decrease in the expression of lumican both at the RNA and protein levels. Lumican is a proteoglycan of the extracellular matrix, belonging to the SLRP (Small Leucine-Rich Repeat Proteoglycans) family. Lumican down-regulation by Endoglin appeared to be controlled, at least in part, at the transcriptional level, as indicated by RT-PCR, and transient transfection experiments using a lumican promoter reporter based vector. This inverse correlation between Endoglin and lumican expression was substantiated by immunohistochemical staining of vessels from human tissues. Thus, cells belonging to the high endothelia, such as tonsil, express a large amount of Endoglin, and the lumican content of their matrix is considerably reduced. Conversely, in resting endothelia, such as that of large vessels, the expression of Endoglin is reduced whereas the amount of lumican is greatly increased. The inverse regulation in the expression of Endoglin and lumican was also evident after TGF-β treatments since Endoglin was up-regulated, whereas lumican was down-regulated by this cytokine. This report describes for the first time a relationship between Endoglin and lumican expression.
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Human Endoglin as a potential new partner involved in platelet–endothelium interactions
Cellular and Molecular Life Sciences, 2017Co-Authors: Elisa Rossi, Miguel Pericacho, Christilla Bachelot-loza, Dominique Pidard, Pascale Gaussem, Consuelo González-manchón, Carmen Langa, Sonia Poirault-chassac, Francisco J. Blanco, Jose M. Lopez NovoaAbstract:Complex interactions between platelets and activated endothelium occur during the thrombo-inflammatory reaction at sites of vascular injuries and during vascular hemostasis. The endothelial receptor Endoglin is involved in inflammation through integrin-mediated leukocyte adhesion and transmigration; and heterozygous mutations in the Endoglin gene cause hereditary hemorrhagic telangiectasia type 1. This vascular disease is characterized by a bleeding tendency that is postulated to be a consequence of telangiectasia fragility rather than a platelet defect, since platelets display normal functions in vitro in this condition. Here, we hypothesize that Endoglin may act as an adhesion molecule involved in the interaction between endothelial cells and platelets through integrin recognition. We find that the extracellular domain of human Endoglin promotes specific platelet adhesion under static conditions and confers resistance of adherent platelets to detachment upon exposure to flow. Also, platelets adhere to confluent endothelial cells in an Endoglin-mediated process. Remarkably, Chinese hamster ovary cells ectopically expressing the human αIIbβ3 integrin acquire the capacity to adhere to myoblast transfectants expressing human Endoglin, whereas platelets from Glanzmann’s thrombasthenia patients lacking the αIIbβ3 integrin are defective for Endoglin-dependent adhesion to endothelial cells. Furthermore, the bleeding time, but not the prothrombin time, is significantly prolonged in Endoglin-haplodeficient (Eng+/−) mice compared to Eng+/+ animals. These results suggest a new role for Endoglin in αIIbβ3 integrin-mediated adhesion of platelets to the endothelium, and may provide a better understanding on the basic cellular mechanisms involved in hemostasis and thrombo-inflammatory events.
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Endoglin regulates mural cell adhesion in the circulatory system
Cellular and Molecular Life Sciences, 2016Co-Authors: Elisa Rossi, David M. Smadja, Miguel Pericacho, Luis Gamella-pozuelo, Carmen Langa, Elisa Boscolo, Luisa-maria Botella, Maria Angeles Arevalo, Alexandre Kauskot, Pascale GaussemAbstract:The circulatory system is walled off by different cell types, including vascular mural cells and podocytes. The interaction and interplay between endothelial cells (ECs) and mural cells, such as vascular smooth muscle cells or pericytes, play a pivotal role in vascular biology. Endoglin is an RGD-containing counter-receptor for β1 integrins and is highly expressed by ECs during angiogenesis. We find that the adhesion between vascular ECs and mural cells is enhanced by integrin activators and inhibited upon suppression of membrane Endoglin or β1-integrin, as well as by addition of soluble Endoglin (SolEng), anti-integrin α5β1 antibody or an RGD peptide. Analysis of different Endoglin mutants, allowed the mapping of the Endoglin RGD motif as involved in the adhesion process. In Eng+/− mice, a model for hereditary hemorrhagic telangectasia type 1, Endoglin haploinsufficiency induces a pericyte-dependent increase in vascular permeability. Also, transgenic mice overexpressing SolEng, an animal model for preeclampsia, show podocyturia, suggesting that SolEng is responsible for podocytes detachment from glomerular capillaries. These results suggest a critical role for Endoglin in integrin-mediated adhesion of mural cells and provide a better understanding on the mechanisms of vessel maturation in normal physiology as well as in pathologies such as preeclampsia or hereditary hemorrhagic telangiectasia.
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0260 : Endoglin in adhesion between endothelial and mural cells
Archives of Cardiovascular Diseases Supplements, 2015Co-Authors: Elisa Rossi, David M. Smadja, Miguel Pericacho, Pascale Gaussem, Carmen Langa, Elisa Boscolo, Luisa-maria Botella, Maria Angeles Arevalo, Alexandre Kauskot, Joyce BischoffAbstract:The interaction and interplay between endothelial cells (ECs) and mural cells (such as vascular smooth muscle cells -VSMCs- and pericytes) play a pivotal role in vascular biology. Endoglin is an RGD-containing ligand of β1 integrins highly expressed by ECs during angiogenesis. Our working hypothesis is that endothelial Endoglin acts as an adhesion molecule via integrin recognition motifs, allowing the interaction between ECs and mural cells. We find that suppression of Endoglin expression or addition of soluble Endoglin inhibits the adhesion between ECs and VSMCs as shown by tubulogenesis assays on matrigel. The EC-VSMC adhesion was also abolished by an antiintegrin α5β1 inhibitory antibody, whereas it was markabsedly enhanced by the integrin activators MnCl2 or CXCL12. The CXCL12-dependent cell adhesion was abolished in the presence of soluble Endoglin or a derived pentapeptide containing the RGD motif. Adhesion of cells overexpressing different Endoglin mutant constructs, allowed the specific mapping of the Endoglin RGD motif as involved in adhesion to VSMCs. Binding of soluble Endoglin to VSMCs was markedly enhanced by MnCl2 and CXCL12 and this increase was inhibited by the RGD peptide. Moreover, transgenic mice overexpressing soluble Endoglin show podocyturia and lower number of glomerular podocytes, suggesting that soluble Endoglin induced the detachment of podocytes from glomerular capillaries. These results suggest a critical role for Endoglin in integrin- mediated adhesion of mural cells and provide a better understanding on the mechanisms of vessel development and maturation in normal physiology as well as in pathologies such as preeclampsia, cancer or hereditary hemorrhagic telangiectasia.
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endothelial Endoglin is involved in inflammation role in leukocyte adhesion and transmigration
Blood, 2013Co-Authors: Elisa Rossi, Carmen Langa, Luisa-maria Botella, Carlos Cabañas, Francisco J. Blanco, Francisco Sanzrodriguez, Nelida Eleno, Annette Duwell, Jose M Lopeznovoa, Carmelo BernabéuAbstract:Human Endoglin is an RGD-containing transmembrane glycoprotein identified in vascular endothelial cells. Although Endoglin is essential for angiogenesis and its expression is upregulated in inflammation and at sites of leukocyte extravasation, its role in leukocyte trafficking is unknown. This function was tested in Endoglin heterozygous mice ( Eng +/- ) and their wild type siblings Eng +/+ treated with carrageenan or LPS as inflammatory agents. Both stimuli showed that inflammation-induced leukocyte trans-endothelial migration to peritoneum or lungs was significantly lower in Eng +/- than in Eng +/+ mice. Leukocyte transmigration through cell monolayers of Endoglin transfectants was clearly enhanced in the presence of Endoglin. Coating transwells with the RGD-containing extracellular domain of Endoglin, enhanced leukocyte transmigration, and this increased motility was inhibited by soluble Endoglin. Leukocytes stimulated with CXCL12, a chemokine involved in inflammation, strongly adhered to Endoglin-coated plates and to Endoglin-expressing endothelial cells. This Endoglin-dependent adhesion was abolished by soluble Endoglin, RGD peptides, the anti-integrin α5β1 inhibitory antibody LIA1/2 and the chemokine receptor inhibitor AMD3100. These results demonstrate for the first time that endothelial Endoglin interacts with leukocyte integrin α5β1 via its RGD motif, and this adhesion process is stimulated by the inflammatory chemokine CXCL12, suggesting a regulatory role for Endoglin in transendothelial leukocyte trafficking.
Michelle Letarte - One of the best experts on this subject based on the ideXlab platform.
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Endoglin: a critical mediator of cardiovascular health.
Vascular health and risk management, 2013Co-Authors: Navin K. Kapur, Kevin J. Morine, Michelle LetarteAbstract:Endoglin (CD105) is a type III auxiliary receptor for the transforming growth factor beta (TGFβ) superfamily. Several lines of evidence suggest that Endoglin plays a critical role in maintaining cardiovascular homeostasis. Seemingly disparate disease conditions, including hereditary hemorrhagic telangiectasia, pre-eclampsia, and cardiac fibrosis, have now been associated with Endoglin. Given the central role of the TGFβ superfamily in multiple disease conditions, this review provides a detailed update on Endoglin as an evolving therapeutic target in the management of cardiovascular disease.
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reduced Endoglin activity limits cardiac fibrosis and improves survival in heart failure
Circulation, 2012Co-Authors: Navin K. Kapur, Szuhuei Wilson, Adil A Yunis, Xiaoying Qiao, Emily E Mackey, Vikram Paruchuri, Corey Baker, Mark Aronovitz, Ananth S Karumanchi, Michelle LetarteAbstract:Background—Heart failure is a major cause of morbidity and mortality worldwide. The ubiquitously expressed cytokine transforming growth factor-β1 (TGFβ1) promotes cardiac fibrosis, an important component of progressive heart failure. Membrane-associated Endoglin is a coreceptor for TGFβ1 signaling and has been studied in vascular remodeling and preeclampsia. We hypothesized that reduced Endoglin expression may limit cardiac fibrosis in heart failure. Methods and Results—We first report that Endoglin expression is increased in the left ventricle of human subjects with heart failure and determined that Endoglin is required for TGFβ1 signaling in human cardiac fibroblasts using neutralizing antibodies and an siRNA approach. We further identified that reduced Endoglin expression attenuates cardiac fibrosis, preserves left ventricular function, and improves survival in a mouse model of pressure-overload–induced heart failure. Prior studies have shown that the extracellular domain of Endoglin can be cleaved and...
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Characterization of murine S-Endoglin isoform and its effects on tumor development
Oncogene, 2005Co-Authors: Eduardo Perez-gomez, Carmelo Bernabéu, José M. López-novoa, Beatriz Velasco, Michelle Letarte, Nelida Eleno, Jose Ramón Ramirez, Miguel QuintanillaAbstract:Endoglin is a transmembrane glycoprotein that acts as an auxiliary receptor for transforming growth factor-β (TGF-β) and modulates cellular responses to this pleiotropic cytokine. Endoglin is strongly expressed in endothelial cells, where it appears to exert a crucial role in vascular development and angiogenesis. Two Endoglin isoforms (L and S), differing in their cytoplasmic domains, have been previously characterized in human tissues. We now demonstrate the existence of similar L- and S-Endoglin variants in murine tissues with 47 and 35 amino acids, respectively, in their cytoplasmic tail. RT–PCR analysis showed that L is the predominant Endoglin isoform expressed in mouse tissues, although S-Endoglin mRNA is significantly expressed in liver and lung, as well as in endothelial cell lines. Furthermore, a protein of size equivalent to recombinant S-Endoglin expressed in mammalian cells was detected in mouse endothelial cells by Western blot analysis. L- and S-Endoglin isoforms can form disulfide-linked heterodimers, as demonstrated by cotransfection of L- and S-Endoglin constructs. To address the role of S-Endoglin in vivo, an S-Eng+ transgenic mouse model that targets S-Endoglin expression to the endothelium was generated. The lethal phenotype of Endoglin-null (Eng−/−) mice was not rescued by breeding S-Eng+ transgenic mice into the Endoglin-null background. S-Eng+ mice exhibited reduced tumor growth and neovascularization after transplantation of Lewis lung carcinoma cells. In addition, S-Eng+ mice showed a drastic inhibition of benign papilloma formation when subjected to two-stage chemical skin carcinogenesis. These results point to S-Endoglin as an antiangiogenic molecule, in contrast to L-Endoglin which is proangiogenic.
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Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor β superfamily
Journal of Biological Chemistry, 1999Co-Authors: Nadia Pece Barbara, Jeffrey L Wrana, Michelle LetarteAbstract:Abstract Endoglin (CD105) is a transmembrane glycoprotein that binds transforming growth factor (TGF)-β1 and -β3, and coprecipitates with the Ser/Thr kinase signaling receptor complex by affinity labeling of endothelial and leukemic cells. The present study shows that in addition to TGF-β1 and -β3, Endoglin interacts with activin-A, bone morphogenetic protein (BMP)-7, and BMP-2 but requires coexpression of the respective ligand binding kinase receptor for this association. Endoglin cannot bind ligands on its own and does not alter binding to the kinase receptors. It binds TGF-β1 and -β3 by associating with the TGF-β type II receptor and interacts with activin-A and BMP-7 via activin type II receptors, ActRII and ActRIIB, regardless of which type I receptor partner is coexpressed. However, Endoglin binds BMP-2 by interacting with the ligand binding type I receptors, ALK3 and ALK6. The formation of heteromeric signaling complexes was not altered by the presence of Endoglin, although it was coprecipitated with these complexes. Endoglin did not interact with BMP-7 through complexes containing the BMP type II receptor, demonstrating specificity of its action. Our data suggest that Endoglin is an accessory protein of multiple kinase receptor complexes of the TGF-β superfamily.
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Endoglin modulates cellular responses to tgf beta 1
Journal of Cell Biology, 1996Co-Authors: Pedro Lastres, Carmen Langa, Ulla Raab, Ainhoa Letamendia, H Zhang, Carlos Rius, Nuria Almendro, Luis Lopez, A Fabra, Michelle LetarteAbstract:Endoglin is a homodimeric membrane glycoprotein which can bind the beta 1 and beta 3 isoforms of transforming growth factor-beta (TGF-beta). We reported previously that Endoglin is upregulated during monocyte differentiation. We have now observed that TGF-beta itself can stimulate the expression of Endoglin in cultured human monocytes and in the U-937 monocytic line. To study the functional role of Endoglin, stable transfectants of U-937 cells were generated which overexpress L- or S- Endoglin isoforms, differing in their cytoplasmic domain. Inhibition of cellular proliferation and downregulation of c-myc mRNA which are normally induced by TGF-beta 1 in U-937 cells were totally abrogated in L-Endoglin transfectants and much reduced in the S-Endoglin transfectants. Inhibition of proliferation by TGF-beta 2 was not altered in the transfectants, in agreement with the isoform specificity of Endoglin. Additional responses of U-937 cells to TGF-beta 1, including stimulation of fibronectin synthesis, cellular adhesion, platelet/endothelial cell adhesion molecule 1 (PECAM-1) phosphorylation, and homotypic aggregation were also inhibited in the Endoglin transfectants. However, modulation of integrin and PECAM-1 levels and stimulation of mRNA levels for TGF-beta 1 and its receptors R-I, R-II, and betaglycan occurred normally in the Endoglin transfectants. No changes in total ligand binding were observed in L-Endoglin transfectants relative to mock, while a 1.5-fold increase was seen in S-Endoglin transfectants. The degradation rate of the ligand was the same in all transfectants. Elucidating the mechanism by which Endoglin modulates several cellular responses to TGF-beta 1 without interfering with ligand binding or degradation should increase our understanding of the complex pathways which mediate the effects of this factor.
Francisco J. Blanco - One of the best experts on this subject based on the ideXlab platform.
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Human Endoglin as a potential new partner involved in platelet–endothelium interactions
Cellular and Molecular Life Sciences, 2017Co-Authors: Elisa Rossi, Miguel Pericacho, Christilla Bachelot-loza, Dominique Pidard, Pascale Gaussem, Consuelo González-manchón, Carmen Langa, Sonia Poirault-chassac, Francisco J. Blanco, Jose M. Lopez NovoaAbstract:Complex interactions between platelets and activated endothelium occur during the thrombo-inflammatory reaction at sites of vascular injuries and during vascular hemostasis. The endothelial receptor Endoglin is involved in inflammation through integrin-mediated leukocyte adhesion and transmigration; and heterozygous mutations in the Endoglin gene cause hereditary hemorrhagic telangiectasia type 1. This vascular disease is characterized by a bleeding tendency that is postulated to be a consequence of telangiectasia fragility rather than a platelet defect, since platelets display normal functions in vitro in this condition. Here, we hypothesize that Endoglin may act as an adhesion molecule involved in the interaction between endothelial cells and platelets through integrin recognition. We find that the extracellular domain of human Endoglin promotes specific platelet adhesion under static conditions and confers resistance of adherent platelets to detachment upon exposure to flow. Also, platelets adhere to confluent endothelial cells in an Endoglin-mediated process. Remarkably, Chinese hamster ovary cells ectopically expressing the human αIIbβ3 integrin acquire the capacity to adhere to myoblast transfectants expressing human Endoglin, whereas platelets from Glanzmann’s thrombasthenia patients lacking the αIIbβ3 integrin are defective for Endoglin-dependent adhesion to endothelial cells. Furthermore, the bleeding time, but not the prothrombin time, is significantly prolonged in Endoglin-haplodeficient (Eng+/−) mice compared to Eng+/+ animals. These results suggest a new role for Endoglin in αIIbβ3 integrin-mediated adhesion of platelets to the endothelium, and may provide a better understanding on the basic cellular mechanisms involved in hemostasis and thrombo-inflammatory events.
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mice lacking Endoglin in macrophages show an impaired immune response
PLOS Genetics, 2016Co-Authors: Luisa Ojedafernandez, Pedro Lastres, Francisco J. Blanco, Francisco Sanzrodriguez, Mikel Aristorena, Angel L. Corbí, Lucia Reciopoveda, Eunate Gallardovara, Mateo De Las Casasengel, Helen M. ArthurAbstract:Endoglin is an auxiliary receptor for members of the TGF-β superfamily and plays an important role in the homeostasis of the vessel wall. Mutations in Endoglin gene (ENG) or in the closely related TGF-β receptor type I ACVRL1/ALK1 are responsible for a rare dominant vascular dysplasia, the Hereditary Hemorrhagic Telangiectasia (HHT), or Rendu-Osler-Weber syndrome. Endoglin is also expressed in human macrophages, but its role in macrophage function remains unknown. In this work, we show that Endoglin expression is triggered during the monocyte-macrophage differentiation process, both in vitro and during the in vivo differentiation of blood monocytes recruited to foci of inflammation in wild-type C57BL/6 mice. To analyze the role of Endoglin in macrophages in vivo, an Endoglin myeloid lineage specific knock-out mouse line (Engfl/flLysMCre) was generated. These mice show a predisposition to develop spontaneous infections by opportunistic bacteria. Engfl/flLysMCre mice also display increased survival following LPS-induced peritonitis, suggesting a delayed immune response. Phagocytic activity is impaired in peritoneal macrophages, altering one of the main functions of macrophages which contributes to the initiation of the immune response. We also observed altered expression of TGF-β1 target genes in Endoglin deficient peritoneal macrophages. Overall, the altered immune activity of Endoglin deficient macrophages could help to explain the higher rate of infectious diseases seen in HHT1 patients.
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Expression of Endoglin isoforms in the myeloid lineage and their role during aging and macrophage polarization
Journal of Cell Science, 2014Co-Authors: Mikel Aristorena, Luisa-maria Botella, Francisco J. Blanco, M. De Las Casas-engel, Luisa Ojeda-fernandez, Eunate Gallardo-vara, Angel L. Corbí, Carmelo BernabéuAbstract:Endoglin plays a crucial role in pathophysiological processes such as hereditary hemorrhagic telangiectasia (HHT), preeclampsia and cancer. Endoglin expression is upregulated during the monocyte-to-macrophage transition, but little is known about its regulation and function in these immune cells. Two different alternatively spliced isoforms of Endoglin have been reported, L-Endoglin and S-Endoglin. Although L-Endoglin is the predominant variant, here, we found that there was an increased expression of the S-Endoglin isoform during senescence of the myeloid lineage in human and murine models. We performed a stable isotope labelling of amino acids in cell culture (SILAC) analysis of both L-Endoglin and S-Endoglin transfectants in the human promonocytic cell line U937. Analysis of differentially expressed protein clusters allowed the identification of cellular activities affected during aging. S-Endoglin expression led to decreased cellular proliferation and a decreased survival response to granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced apoptosis, as well as increased oxidative stress. Gene expression and functional studies suggested that there was a non-redundant role for each Endoglin isoform in monocyte biology. In addition, we found that S-Endoglin impairs the monocytic differentiation into the pro-inflammatory M1 phenotype and contributes to the compromised status of macrophage functions during aging.
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endothelial Endoglin is involved in inflammation role in leukocyte adhesion and transmigration
Blood, 2013Co-Authors: Elisa Rossi, Carmen Langa, Luisa-maria Botella, Carlos Cabañas, Francisco J. Blanco, Francisco Sanzrodriguez, Nelida Eleno, Annette Duwell, Jose M Lopeznovoa, Carmelo BernabéuAbstract:Human Endoglin is an RGD-containing transmembrane glycoprotein identified in vascular endothelial cells. Although Endoglin is essential for angiogenesis and its expression is upregulated in inflammation and at sites of leukocyte extravasation, its role in leukocyte trafficking is unknown. This function was tested in Endoglin heterozygous mice ( Eng +/- ) and their wild type siblings Eng +/+ treated with carrageenan or LPS as inflammatory agents. Both stimuli showed that inflammation-induced leukocyte trans-endothelial migration to peritoneum or lungs was significantly lower in Eng +/- than in Eng +/+ mice. Leukocyte transmigration through cell monolayers of Endoglin transfectants was clearly enhanced in the presence of Endoglin. Coating transwells with the RGD-containing extracellular domain of Endoglin, enhanced leukocyte transmigration, and this increased motility was inhibited by soluble Endoglin. Leukocytes stimulated with CXCL12, a chemokine involved in inflammation, strongly adhered to Endoglin-coated plates and to Endoglin-expressing endothelial cells. This Endoglin-dependent adhesion was abolished by soluble Endoglin, RGD peptides, the anti-integrin α5β1 inhibitory antibody LIA1/2 and the chemokine receptor inhibitor AMD3100. These results demonstrate for the first time that endothelial Endoglin interacts with leukocyte integrin α5β1 via its RGD motif, and this adhesion process is stimulated by the inflammatory chemokine CXCL12, suggesting a regulatory role for Endoglin in transendothelial leukocyte trafficking.
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s Endoglin expression is induced in senescent endothelial cells and contributes to vascular pathology
Circulation Research, 2008Co-Authors: Francisco J. Blanco, María T. Grande, Carmen Langa, Barbara Oujo, Soraya Velasco, Miguel Quintanilla, Jose M Lopeznovoa, Alicia Rodriguezbarbero, Eduardo Perezgomez, Carmelo BernabéuAbstract:Senescence of endothelial cells (ECs) may contribute to age-associated cardiovascular diseases, including atherosclerosis and hypertension. The functional and gene expression changes associated with cellular senescence are poorly understood. Here, we have analyzed the expression, during EC senescence, of 2 different isoforms (L, long; S, short) of Endoglin, an auxiliary transforming growth factor (TGF)-β receptor involved in vascular remodeling and angiogenesis. As evidenced by RT-PCR, the S/L ratio of Endoglin isoforms was increased during senescence of human ECs in vitro, as well as during aging of mice in vascularized tissues. Next, the effect of S-Endoglin protein on the TGF-β receptor complex was studied. As revealed by coimmunoprecipitation assays, S-Endoglin was able to interact with both TGF-β type I receptors, ALK5 and ALK1, although the interaction with ALK5 was stronger than with ALK1. S-Endoglin conferred a lower proliferation rate to ECs and behaved differently from L-Endoglin in relation to ...