Cellular and molecular biology of the vascular endothelium

Description

The objective of the laboratory is to study the role of endoglin in pathophysiology. Endoglin is a homodimeric membrane glycoprotein with a size of 180-kDa. It is highly expressed in endothelial cells and syncytiotrophoblasts, and at lower levels in activated monocytes/macrophages, as well as in mesenchymal stem cells, fibroblasts, and vascular smooth muscle cells. In endothelial cells, endoglin is a component of the receptor complex for the transforming growth factor (TGF-β) family, and it is also involved in integrin-mediated cell adhesion.

The TGF-β family includes the bone morphogenetic proteins (BMPs), activins, and TGF-β subfamilies. Members of the TGF-β family exert their biological functions through a receptor complex that includes serine/threonine kinases type I (TβRI) and type II (TβRII) and the auxiliary receptors endoglin or betaglycan. On endothelial cells, endoglin and ALK1 (a type of TβRI) in this complex act as receptors for BMP9, BMP10, and other family members. After ligand binding to the receptor complex, ALK1 initiates the signaling pathway by phosphorylation of the Smad family of proteins. On the other hand, endothelial endoglin is an adhesion receptor that interacts with integrins of leukocytes, platelets and vascular mural cells. The participation of endoglin in these signaling pathways is crucial for the regulation of various pathophysiological processes, including those related to the cardiovascular system. In this context, endoglin is associated with a wide range of conditions, including physiological and pathological angiogenesis, vascular pathology, preeclampsia, tumor vascularization, hemostasis or tumor malignancy.

Endoglin has important implications in vascular pathophysiology. Thus, mutations in the endoglin gene are responsible for Hereditary Hemorrhagic Telangiectasia type 1 (HHT1), an autosomal dominant vascular dysplasia associated with frequent epistaxis, gastrointestinal hemorrhages, cutaneous telangiectasias, and arteriovenous malformations in the lung, liver, and brain. Endoglin plays an important role in vascular remodeling and cardiovascular development. Its expression is regulated during heart development; it is highly increased in the endocardium during valve formation and in mesenchymal cells of the atrioventricular canal during the formation of the heart septum. Its role in morphogenesis has been confirmed by the finding that mouse embryos homozygous for an endoglin mutant die at 10-10.5 days postcoitus due to vascular and cardiac anomalies. Furthermore, endoglin plays a role in vascular homeostasis by regulating nitric oxide-dependent vasodilation, and is an integrin ligand involved in endothelial cell adhesion processes during pathological inflammatory conditions and in primary hemostasis. Furthermore, a circulating form of endoglin, also called soluble endoglin, whose levels increase abnormally in different pathological conditions, such as preeclampsia, appears to act as an antagonist of membrane-bound endoglin and as a competitor of the fibrinogen-integrin interaction in platelet-dependent thrombus formation. These studies suggest that membrane-bound endoglin and circulating endoglin are important components involved in vascular homeostasis and hemostasis.

Despite its importance in human pathophysiology, the mechanisms by which endoglin acts in these biological processes and diseases are largely unknown. Our current line of research aims to deepen our knowledge on the expression, structure and function of endoglin, which will allow us to better understand the molecular mechanisms by which this protein is involved in human pathology.

Hereditary hemorrhagic telangiectasia (HHT) and the TGF-β system in endothelial cells. Heterodimers of BMP9/BMP10 bind to a protein complex composed by type I (R-I) and type II (R-II) receptors, and endoglin. Upon ligand binding, Smad proteins translocate into the nucleus. BMP9, Endoglin, ALK1, and Smad4 proteins are encoded by GDF2, ENG, ACVRL1, and MADH4 genes, whose mutations give rise to HHT5, HHT1, HHT2, and JPHT, respectively. Adapted from Bernabeu et al. [2020].

Hypothetical model for BMP4 in sEng-dependent effect in hypertension. Upon inflammation, MMP12 or MMP14 trigger the release of sEng in endothelial cells by proteolytically cleaving membrane-bound endoglin. In turn, sEng stimulates the expression of BMP4 in different organs, including lung, stomach and duodenum. Next, circulating BMP4 contributes to endothelial dysfunction, leading to hypertension. Adapted from Gallardo-Vara et al (2020).

Staff Scientists
Carmelo Bernabeu Quirante

Visitors
Lidia Ruiz Llorente

Bernabeu C, Olivieri C, Rossi E. [2023]. Editorial: Role of membrane-bound and circulating endoglin in disease. Front Med (Lausanne). 2023 Sep 4; 10:1271756. doi: 10.3389/fmed.2023.1271756.

Rossi E, Bernabeu C. [2023]. Novel Vascular Roles of Human Endoglin in Pathophysiology. J. Thromb. Haemost. 2023 Sep; 21(9):2327-2338. doi: 10.1016/j.jtha.2023.06.007.

Bernabeu C. [2023]. Therapeutic Targeting of the Ang2/Tie Pathway in Endothelial Cells as a Potential Treatment of Hereditary Hemorrhagic Telangiectasia. Arterioscler. Thromb. Vasc. Biol. 2023 Aug; 43(8):1404-1408. doi: 10.1161/ATVBAHA.123.319631.

Rossi E, Pericacho M, Kauskot A, Gamella-Pozuelo L, Reboul E, Leuci A, Egido-Turrion C, El Hamaoui D, Marchelli A, Fernández FJ, Margaill I, Vega MC, Gaussem P, Pasquali S, Smadja DM, Bachelot-Loza C, Bernabeu C. [2023]. Soluble endoglin reduces thrombus formation and platelet aggregation via interaction with αIIbβ3 integrin. J. Thromb. Haemost. 2023 Jul; 21(7):1943-1956. doi: 10.1016/j.jtha.2023.03.023.

Ruiz-Llorente L, Ruiz-Rodríguez MJ, Savini C, González-Muñoz T, Riveiro-Falkenbach E, Rodríguez-Peralto JL, Peinado H, Bernabeu C. [2023]. Correlation Between Endoglin and Malignant Phenotype in Human Melanoma Cells: Analysis of hsa-mir-214 and hsa-mir-370 in Cells and Their Extracellular Vesicles. Adv. Exp. Med. Biol. 2023; 1408:253-272. doi: 10.1007/978-3-031-26163-3_14.

Felipe Simon and Carmelo Bernabeu, Editors. [2023]. Advances in Molecular Pathology. Book series: Advances in Experimental Medicine and Biology (AEMB, volume 1408). Publisher Springer-Nature, Cham, Switzerland. ISBN 978-3-031-26163-3 (eBook). April 2023. doi: https://doi.org/10.1007/978-3-031-26163-3.

Tripska K, Igreja Sá IC, Vasinova M, Vicen M, Havelek R, Eissazadeh S, Svobodova Z, Vitverova B, Theuer C, Bernabeu C, Nachtigal P. [2022]. Monoclonal anti-endoglin antibody TRC105 (carotuximab) prevents hypercholesterolemia and hyperglycemia-induced endothelial dysfunction in human aortic endothelial cells. Front. Med. (Lausanne). 2022 Sep 7; 9:845918. doi: 10.3389/fmed.2022.845918.

Puerto-Camacho P, Díaz-Martín J, Olmedo-Pelayo J, Bolado-Carrancio A, Salguero-Aranda C, Jordán-Pérez C, Esteban-Medina M, Álamo-Álvarez I, Delgado-Bellido D, Lobo-Selma L, Dopazo J, Sastre A, Alonso J, Grünewald TGP, Bernabeu C, Byron A, Brunton VG, Amaral AT, de Álava E. [2022]. Endoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell-Matrix Interactions. Int. J. Mol. Sci. 2022 Aug 4; 23(15):8657. doi: 10.3390/ijms23158657.

Egido-Turrión C, Rossi E, Ollauri-Ibáñez C, Pérez-García ML, Sevilla MA, Bastida JM, González-Porras JR, Rodríguez-Barbero A, Bernabeu C, Lopez-Novoa JM, Pericacho M. [2022]. Functional Alterations Involved in Increased Bleeding in Hereditary Hemorrhagic Telangiectasia Mouse Models. Front. Med. (Lausanne). 2022 May 19; 9:871903. doi: 10.3389/fmed.2022.871903.

Luque J, Mendes I, Gómez B, Morte B, de Heredia ML, Herreras E, Corrochano V, Bueren J, Gallano P, Artuch R, Fillat C, Pérez-Jurado LA, Montoliu L, Carracedo Á, Millán JM, Webb SM, Palau F; CIBERER Network, Lapunzina P. [2022]. CIBERER: Spanish National Network for Research on Rare Diseases: a highly productive collaborative initiative. Clin. Genet. 2022 May; 101(5-6): 481-493. doi: 10.1111/cge.14113.

All Publications

201920E039 del Consejo Superior de Investigaciones Cientificas. "Análisis proteómico de endoglina humana y proteinas asociadas ". Periodo: 20 Enero 2019 a 19 Enero 2022. Centro de Investigaciones Biológicas, CSIC. Madrid. Investigador Principal: Carmelo Bernabéu Quirante.

PRX17/00142 del Programa Salvador de Madariaga, Ministerio de Educacion, Cultura y Deporte. "Identificación y caracterización de nuevos genes implicados en la Telangiectasia Hemorrágica Hereditaria". Periodo: 2 Abril 2018-30 Septiembre 2018. Investigador Principal: Carmelo Bernabéu Quirante.

ER16P1AC707/2016 del Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER). "Análisis de una nueva función de endoglina en adhesión celular y su relevancia en la fisiopatología de la Telangiectasia Hemorrágica Hereditaria". Periodo: 1 Enero-31 Diciembre 2016. Centro de Investigaciones Biológicas, CSIC. Madrid. Investigador Principal: Carmelo Bernabéu Quirante.

201420E039 del Consejo Superior de Investigaciones Cientificas. "Analisis de un nuevo papel de endoglina en adhesion celular y su relevancia en biología vascular". Periodo: 15 Marzo 2014 a 14 Septiembre 2018. Centro de Investigaciones Biológicas, CSIC. Madrid. Investigador Principal: Carmelo Bernabéu Quirante.

SAF2013-43421-R del Ministerio de Economía y Competitividad, Programa Estatal de Investigación, Desarrollo e Innovación Orientada a los Retos de la Sociedad: “Análisis de un nuevo rol de endoglina en adhesion celular y su relevancia en la biología vascular”. Periodo: 1 Enero 2014 a 30 Junio 2018. Centro de Investigaciones Biológicas, CSIC. Madrid. Investigador Principal: Carmelo Bernabéu Quirante.

SAF2010-19222 del Ministerio de Ciencia e Innovación, Plan Nacional de I+D: “Estudios moleculares sobre endoglina y ALK1, dos componentes del receptor endotelial de TGF-beta implicados en la fisiopatología vascular”. Periodo: 1 Enero 2011 a 31 Diciembre 2013 (prorrogado hasta 31 Diciembre 2014). Centro de Investigaciones Biológicas, CSIC. Madrid. Investigador Principal: Carmelo Bernabéu Quirante.

MEICA de Genoma España. “Molecular and cellular mechanisms in chronic inflammatory and autoimmune diseases”. Periodo: 15 Enero 2009 a 30 Septiembre 2012. Centro de Investigaciones Biológicas, CSIC. Madrid. Coordinador científico: Francisco Sanchez Madrid. Investigador Principal subproyecto: Carmelo Bernabéu Quirante.

INTRA/08/707.1 del Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER). "Estudio de endoglina como nueva diana de las terapias relacionadas con angiogénesis". Periodo: 2008-2009. Centro de Investigaciones Biológicas, CSIC. Madrid. Investigador Principal: Carmelo Bernabéu Quirante.

INTRA/07/739.1 del Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER). "Bases estructurales de enfermedades raras metabólicas, endovasculares y de la hemostasia". Periodo: 2007-2009. Centro de Investigaciones Biológicas, CSIC. Madrid. Coordinador: Vicente Rubio Zamora. Investigador Principal subproyecto unidad 707 CIBERER: Carmelo Bernabéu Quirante.

ISCIII-CB06/07/0038. Desde Junio 2006 nuestro grupo de investigación (unidad 707) forma parte del Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Ministerio de Economia, Industria y Competitividad.

SAF2007-61827 del Ministerio de Ciencia e Innovacion, Plan Nacional de I+D: “Mecanismos moleculares del receptor de TGF-beta endotelial en la fisiopatologia vascular”. Período Octubre 2007-Octubre 2010. Centro de Investigaciones Biológicas, CSIC. Madrid. Investigador Principal: Carmelo Bernabéu Quirante.

HHT Foundation International, Inc., Monkton, MD, USA. "Primary cultures of endothelial and monocytic cells derived from HHT patients: An open window to unravel the pathogenicity of HHT" Periodo: Julio 2005-Julio 2006. Investigador Principal: Carmelo Bernabéu Quirante.

SAF2004-01390 del Ministerio de Educacion y Ciencia, Plan Nacional de I+D: “Estudios sobre endoglina, un co-receptor de TGF-beta implicado en la patologia humana”. Período Diciembre 2004-Diciembre 2007. Centro de Investigaciones Biológicas, CSIC. Madrid. Investigador Principal: Carmelo Bernabéu Quirante.

08.4/0026.1/2003 de la Conserjería de Educación y Cultura de la Comunidad de Madrid: "Mutaciones y regulación del gen de endoglina en la HHT" Período: Octubre 2003-Octubre 2004. Centro de Investigaciones Biológicas, CSIC Madrid. Investigador Principal: Carmelo Bernabéu Quirante.

PI020200 del Plan Nacional de Investigación Científica, Desarrollo e Innovación tecnológica (I+D+I). Instituto de Salud Carlos III, Fondo de Investigación Sanitaria, “Bases moleculares de la telangiectasia Hemorrágica hereditaria. Detección y relevancia funcional de mutaciones en el gen de endoglina”. Período Noviembre 2002-Julio 2005. Centro de Investigaciones Biológicas, CSIC. Madrid. Investigador Principal: Carmelo Bernabéu Quirante. Importe: 129.500 euros.

08.4/0029/2000 de la Conserjería de Educación y Cultura de la Comunidad de Madrid: "Función y expresión de endoglina, un receptor endotelial implicado en la remodelación vascular" Período: Enero 2001-Diciembre 2002. Centro de Investigaciones Biológicas, CSIC Madrid. Investigador Principal: Carmelo Bernabéu Quirante.

Institut National de la Santé et de la Recherche Medicale (INSERM) y Association Française contre les Myopathies (AFM) "Coordination d´un reseau de recherche sur la maladie de Rendu-Osler: etudes clinique, genetique, physiopathologique et therapeutique d´une pathologie hereditaire rare de l´angiongenese" Período: 2001-2004. Coordinador general: Henri Plauchu. Investigador subproyecto: Carmelo Bernabéu Quirante.

SAF2000-0132 del Ministerio de Ciencia y Tecnología, Plan Nacional de I+D: “Endoglina, un receptor endotelial implicado en la remodelación vascular”. Período 2000-2003. Centro de Investigaciones Biológicas, CSIC. Madrid. Investigador Principal: Carmelo Bernabéu Quirante.

08.4/0020.1/99 de la Conserjería de Educación y Cultura de la Comunidad de Madrid: "Papel de endoglina, un receptor para TGF-β, en la vascularización" Período: Enero-Diciembre 2000. Centro de Investigaciones Biológicas, CSIC Madrid. Investigador Principal: Carmelo Bernabéu Quirante.

SAF97-0034 de la Comisión Interministerial de Ciencia y Tecnología, Plan Nacional de Investigación Científica y Desarrollo Tecnológico: “Papel de TGF-β y sus receptores en proliferación, diferenciación y adhesión celulares”. Período 1997-2000. Centro de Investigaciones Biológicas, CSIC. Madrid. Investigador Principal: Carmelo Bernabéu Quirante.

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Group Leader/s

Carmelo Bernabeu Quirante

intro

Research lines

Endoglin, an endothelial receptor involved in vascular pathology

Members

Selected Publications

Bernabeu C, Olivieri C, Rossi E. [2023]. Editorial: Role of membrane-bound and circulating endoglin in disease. Front Med (Lausanne). 2023 Sep 4; 10:1271756. doi: 10.3389/fmed.2023.1271756.

Rossi E, Bernabeu C. [2023]. Novel Vascular Roles of Human Endoglin in Pathophysiology. J. Thromb. Haemost. 2023 Sep; 21(9):2327-2338. doi: 10.1016/j.jtha.2023.06.007.

Bernabeu C. [2023]. Therapeutic Targeting of the Ang2/Tie Pathway in Endothelial Cells as a Potential Treatment of Hereditary Hemorrhagic Telangiectasia. Arterioscler. Thromb. Vasc. Biol. 2023 Aug; 43(8):1404-1408. doi: 10.1161/ATVBAHA.123.319631.

Funding

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