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ResearchIn-Press PreviewAgingVascular biology Open Access | 10.1172/JCI173448

Endothelial YAP/TAZ activation promotes atherosclerosis in a mouse model of Hutchinson-Gilford progeria syndrome

Ana Barettino,1 Cristina González-Gómez,1 Pilar Gonzalo,2 María J. Andrés-Manzano,1 Carlos R. Guerrero,3 Francisco M. Espinosa,3 Rosa M. Carmona,1 Yaazan Blanco,1 Beatriz Dorado,1 Carlos Torroja,4 Fátima Sánchez-Cabo,4 Ana Quintas,5 Alberto Benguría,5 Ana Dopazo,5 Ricardo García,3 Ignacio Benedicto,1 and Vicente Andrés1

1Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

2Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

3Nanoscience and Nanotechnology, Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

4Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

5Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

Find articles by Barettino, A. in: JCI | PubMed | Google Scholar

1Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

2Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

3Nanoscience and Nanotechnology, Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

4Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

5Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

Find articles by González-Gómez, C. in: JCI | PubMed | Google Scholar

1Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

2Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

3Nanoscience and Nanotechnology, Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

4Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

5Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

Find articles by Gonzalo, P. in: JCI | PubMed | Google Scholar

1Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

2Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

3Nanoscience and Nanotechnology, Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

4Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

5Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

Find articles by Andrés-Manzano, M. in: JCI | PubMed | Google Scholar

1Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

2Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

3Nanoscience and Nanotechnology, Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

4Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

5Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

Find articles by Guerrero, C. in: JCI | PubMed | Google Scholar

1Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

2Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

3Nanoscience and Nanotechnology, Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

4Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

5Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

Find articles by Espinosa, F. in: JCI | PubMed | Google Scholar

1Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

2Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

3Nanoscience and Nanotechnology, Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

4Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

5Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

Find articles by Carmona, R. in: JCI | PubMed | Google Scholar

1Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

2Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

3Nanoscience and Nanotechnology, Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

4Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

5Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

Find articles by Blanco, Y. in: JCI | PubMed | Google Scholar

1Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

2Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

3Nanoscience and Nanotechnology, Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

4Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

5Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

Find articles by Dorado, B. in: JCI | PubMed | Google Scholar

1Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

2Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

3Nanoscience and Nanotechnology, Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

4Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

5Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

Find articles by Torroja, C. in: JCI | PubMed | Google Scholar

1Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

2Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

3Nanoscience and Nanotechnology, Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

4Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

5Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

Find articles by Sánchez-Cabo, F. in: JCI | PubMed | Google Scholar |

1Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

2Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

3Nanoscience and Nanotechnology, Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

4Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

5Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

Find articles by Quintas, A. in: JCI | PubMed | Google Scholar |

1Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

2Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

3Nanoscience and Nanotechnology, Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

4Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

5Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

Find articles by Benguría, A. in: JCI | PubMed | Google Scholar |

1Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

2Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

3Nanoscience and Nanotechnology, Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

4Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

5Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

Find articles by Dopazo, A. in: JCI | PubMed | Google Scholar |

1Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

2Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

3Nanoscience and Nanotechnology, Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

4Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

5Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

Find articles by García, R. in: JCI | PubMed | Google Scholar

1Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

2Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

3Nanoscience and Nanotechnology, Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

4Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

5Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

Find articles by Benedicto, I. in: JCI | PubMed | Google Scholar

1Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

2Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

3Nanoscience and Nanotechnology, Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

4Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

5Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

Find articles by Andrés, V. in: JCI | PubMed | Google Scholar

Published October 1, 2024 - More info

J Clin Invest. https://doi.org/10.1172/JCI173448.
Copyright © 2024, Barettino et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 1, 2024 - Version history
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Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare disease caused by the expression of progerin, an aberrant protein produced by a point mutation in the LMNA gene. HGPS patients show accelerated aging and die prematurely mainly from complications of atherosclerosis such as myocardial infarction, heart failure, or stroke. However, the mechanisms underlying HGPS vascular pathology remain ill defined. We used single-cell RNA sequencing to characterize the aorta in progerin-expressing LmnaG609G/G609G mice and wild-type controls, with a special focus on endothelial cells (ECs). HGPS ECs showed gene expression changes associated with extracellular matrix alterations, increased leukocyte extravasation, and activation of the yes-associated protein 1/transcriptional activator with PDZ-binding domain (YAP/TAZ) mechanosensing pathway, all validated by different techniques. Atomic force microscopy experiments demonstrated stiffer subendothelial extracellular matrix in progeroid aortas, and ultrasound assessment of live HGPS mice revealed disturbed aortic blood flow, both key inducers of the YAP/TAZ pathway in ECs. YAP/TAZ inhibition with verteporfin reduced leukocyte accumulation in the aortic intimal layer and decreased atherosclerosis burden in progeroid mice. Our findings identify endothelial YAP/TAZ signaling as a key mechanism of HGPS vascular disease and open a new avenue for the development of YAP/TAZ targeting drugs to ameliorate progerin-induced atherosclerosis.

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Version history
  • Version 1 (October 1, 2024): In-Press Preview
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