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Endothelial YAP/TAZ activation promotes atherosclerosis in a mouse model of Hutchinson-Gilford progeria syndrome
Ana Barettino, … , Ignacio Benedicto, Vicente Andrés
Ana Barettino, … , Ignacio Benedicto, Vicente Andrés
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(22):e173448. https://doi.org/10.1172/JCI173448.
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Research Article Aging Vascular biology

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

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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 aortae, 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.

Authors

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

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Figure 5

Blood flow alterations in the aorta of LmnaG609G/G609G mice.

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Blood flow alterations in the aorta of LmnaG609G/G609G mice.
(A) Represe...
(A) Representative ultrasound images of descending aorta. Magnified views show pulse-wave Doppler mode graphs, with mean velocity in systole indicated with blue dashed lines (below baseline); in progeroid mice, retrograde flow in diastole is detected as a plateau above baseline (blue arrowhead). (B) Percentage of mice with aortic insufficiency (retrograde flow) in the descending aorta: 0 of 10 Lmna+/+ mice; 5 of 10 LmnaG609G/G609G mice. (C) Blood flow mean velocity values in the indicated aortic regions (n = 9–10). (D) Pulsatility index and resistive index in abdominal aorta (n = 10). (E) Representative en face immunofluorescence images of thoracic aortae, showing ECs (CD31, green), Golgi apparatus (GLG1, white), and nuclei (Hoechst 33342, blue), and percentage of ECs with mispolarized Golgi apparatus (downstream orientation relative to nuclei, arrowheads) (n = 6). Mean values for each mouse were determined by averaging of values from 3 fields. (F) Representative en face immunofluorescence images of thoracic aortae, showing ECs (CD31, green), primary cilia (ARL13B, white), and nuclei (Hoechst 33342, blue), and percentage of ciliated ECs (arrowheads) (n = 12). Mean values for each mouse were determined by averaging of values from 3 fields. (G and H) Overlap between gene expression changes in progeroid aortic ECs (C6 cluster in Figure 1, LmnaG609G/G609G vs. Lmna+/+ mice) and wild-type carotid ECs exposed to disturbed blood flow (carotid partial ligation vs. sham, results reported in ref. 25). Red dots in H highlight YAP/TAZ downstream targets significantly upregulated in both conditions. Data in C–F are shown as mean + SD. Statistical analysis was performed by 2-sided Fisher’s exact test (B) and unpaired 2-tailed Student’s t test (C–F). Outliers assessed by ROUT test in C and D were excluded for analysis. Scale bars: 50 μm. *P < 0.05, **P < 0.01, ****P < 0.0001. CPL, carotid partial ligation; DEG, differentially expressed genes; FC, fold change; GA, Golgi apparatus.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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