Publication: Endoglina soluble: mecanismo de generación y función en células endoteliales y su efecto en el remodelado vascular
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2018-09-05
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Universidad Complutense de Madrid
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Abstract
Endoglina es una glicoproteína homodimérica transmembrana que cumple un papel fundamental en la angiogénesis y remodelado vascular, actuando como co-receptor en la señalización de TGF-β de la célula endotelial y modulando la vía de señalización a través de ALK-1/ALK5. Mutaciones en heterocigosis del gen de endoglina causan una enfermedad rara conocida como Telangiectasia Hemorrágica Hereditaria (HHT), caracterizada por sangrados recurrentes y malformaciones arteriovenosas. En HHT, el daño endotelial se ha postulado como uno de los posibles “segundos eventos” necesarios para que se produzcan estas malformaciones arteriovenosas. Bajo un daño endotelial el factor de transcripción Krüppel-like-factor 6 (KLF6) se transloca al núcleo para regular diferentes genes diana involucrados en reparación endotelial, incluyendo entre ellos componentes de la familia de TGF-β como endoglina y ALK1. Mientras que la mayoría de los estudios sobre endoglina se han focalizado en sus isoformas de membrana, poco se conoce de la regulación y el papel que puede jugar la endoglina soluble. Se sabe que es liberada al medio como consecuencia del corte de endoglina de membrana por la metaloproteinasa MMP14 en las células endoteliales; que está aumentada en diversas patologías cardiovasculares, inflamatorias y tumorales; y que tiene, principalmente, una función antiangiogénica. El hecho de que algunos de los medicamentos usados en el tratamiento para HHT tengan propiedades antiangiogénicas, plantea la cuestión de si endoglina soluble puede tener también una acción beneficiosa en la prevención y tratamiento de las malformaciones arteriovenosas...
Endoglin is a transmembrane homodimeric glycoprotein that plays a key role in angiogenesis and vascular remodeling, acting as a co-receptor of TGF-β family members in endothelial cells, and modulating the TGF-β signaling pathway through ALK-1 / ALK5. Mutations in endoglin gene are responsible for a rare disease known as Hereditary Hemorrhagic Telangiectasia (HHT), associated with recurrent bleedings and arteriovenous malformations. Endothelial damage in HHT has been postulated as one of the possible "second events" necessary for the formation of arteriovenous malformations. Under endothelial damage, the transcription factor Krüppel-Like-Factor 6 (KLF6) translocates into the cell nucleus to regulate a variety of target genes involved in endothelial repair and vascular remodeling, including components of the membrane TGF-β receptor family complex such as endoglin and ALK1. While most of endoglin studies have focused on the two membrane isoforms, the regulation and role of soluble endoglin are poorly understood. It is already known that membrane metalloproteinase 14 (MMP14) targets membrane endoglin in endothelial cells to release soluble endoglin to the medium. Soluble endoglin is involved in many cardiovascular, inflammatory and tumor pathologies, and it is known to have an antiangiogenic function. The fact that some of the treatments used for HHT have antiangiogenic properties raises the question of whether this soluble endoglin can modulate the arteriovenous malformations...
Endoglin is a transmembrane homodimeric glycoprotein that plays a key role in angiogenesis and vascular remodeling, acting as a co-receptor of TGF-β family members in endothelial cells, and modulating the TGF-β signaling pathway through ALK-1 / ALK5. Mutations in endoglin gene are responsible for a rare disease known as Hereditary Hemorrhagic Telangiectasia (HHT), associated with recurrent bleedings and arteriovenous malformations. Endothelial damage in HHT has been postulated as one of the possible "second events" necessary for the formation of arteriovenous malformations. Under endothelial damage, the transcription factor Krüppel-Like-Factor 6 (KLF6) translocates into the cell nucleus to regulate a variety of target genes involved in endothelial repair and vascular remodeling, including components of the membrane TGF-β receptor family complex such as endoglin and ALK1. While most of endoglin studies have focused on the two membrane isoforms, the regulation and role of soluble endoglin are poorly understood. It is already known that membrane metalloproteinase 14 (MMP14) targets membrane endoglin in endothelial cells to release soluble endoglin to the medium. Soluble endoglin is involved in many cardiovascular, inflammatory and tumor pathologies, and it is known to have an antiangiogenic function. The fact that some of the treatments used for HHT have antiangiogenic properties raises the question of whether this soluble endoglin can modulate the arteriovenous malformations...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Bioquímica y Biología Molecular I, leída el 16-06-2017