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MiR-205 is downregulated in hereditary hemorrhagic telangiectasia and impairs TGF-beta signaling pathways in endothelial cells

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Abstract

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by arteriovenous malformations and hemorrhages. This vascular disease results mainly from mutations in 2 genes involved in the TGF-β pathway (ENG and ALK1) that are exclusively expressed by endothelial cells. The present study identified miR-27a and miR-205 as two circulating miRNAs differentially expressed in HHT patients. The plasma levels of miR-27a are elevated while those of miR-205 are reduced in both HHT1 and HHT2 patients compared to healthy controls. The role of miR-205 in endothelial cells was further investigated. Our data indicates that miR-205 expression displaces the TGF-β balance towards the anti-angiogenic side by targeting Smad1 and Smad4. In line, overexpression of miR-205 in endothelial cells reduces proliferation, migration and tube formation while its inhibition shows opposite effects. This study not only suggests that detection of circulating miRNA (miR-27a and miR-205) could help for the screening of HHT patients but also provides a functional link between the deregulated expression of miR-205 and the HHT phenotype.

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Acknowledgments

We thank Michelle Lion, Jean-Yves Carabin and Olivier Nivelles for technical assistance. This study was supported by the University of Liège (Fonds Speciaux), le centre anti-cancéreux (CAC ULg), the FRIA (Fonds pour la Recherche Industrielle et Agricole, Belgium), the FNRS (Fonds National de la Recherche Scientifique, Belgium), the Neoangio program #616476 of the “Service Public de Wallonie”, la “fédération belge contre le cancer”. This work was supported by the Ministerio de Ciencia e Innovacion: Grants SAF2008–01218, SAF2011-23475, SAF2007–61827, and SAF2010–19222, and Fundación Ramón Areces of Spain (Rare and Emergent Diseases). CIBERER is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain. L Ojeda-Fernandez is recipient of a CIBERER contract.

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The authors declare that thy have no conflict of interest.

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Authors and Affiliations

  1. Unit of Molecular Biology and Genetic Engineering, GIGA, University of Liège, Sart-Tilman, 4000, Liège, Belgium

    Sebastien P. Tabruyn, Sylvain Hansen, Nicolas Bovy, Joseph A. Martial & Ingrid Struman

  2. Centro de Investigaciones Biológicas (CIB), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

    Maria-Luisa Ojeda-Fernández, Lucia Recio-Poveda, Carmelo Bernabéu & Luisa-Maria Botella

  3. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

    Maria-Luisa Ojeda-Fernández, Lucia Recio-Poveda, Carmelo Bernabéu & Luisa-Maria Botella

  4. Department of Internal Medicine, Hospital de Sierrallana, Torrelavega, Spain

    Roberto Zarrabeitia

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  1. Sebastien P. Tabruyn
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Correspondence to Ingrid Struman.

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Tabruyn, S.P., Hansen, S., Ojeda-Fernández, ML. et al. MiR-205 is downregulated in hereditary hemorrhagic telangiectasia and impairs TGF-beta signaling pathways in endothelial cells. Angiogenesis 16, 877–887 (2013). https://doi.org/10.1007/s10456-013-9362-9

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