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

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 6

EC-specific progerin expression is not sufficient to trigger YAP/TAZ activation and leukocyte recruitment.

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EC-specific progerin expression is not sufficient to trigger YAP/TAZ act...
(A) Representative images of en face immunofluorescence staining in thoracic aorta showing ECs (CD31, green), progerin (white), leukocytes (CD45.2, red), and nuclei (Hoechst 33342, blue), and percentage of progerin+ ECs. Mean value per mouse (n = 8–9) was determined by averaging of cells from 1 field. (B) Young’s modulus determined by atomic force microscopy (n = 9). (C) Frequency distribution of Young’s modulus (n = 9). (D) Masson’s trichrome staining of thoracic aorta to quantify percentage of collagen area in the luminal region (first 10 μm from the lumen) and in the remaining medial aorta (non-luminal) (n = 9–11). (E) Representative ultrasound images of descending aorta. (F) Percentage of mice with aortic insufficiency (retrograde flow) in descending aorta (0 of 10 in LmnaLCS/LCS and LmnaLCS/LCS Tie2Cre). (G) Blood flow mean velocity at indicated aortic regions (n = 10). (H) Expression of YAP/TAZ target genes in thoracic aorta ECs quantified by RT-qPCR (n = 7). (I) Representative en face immunofluorescence images of thoracic aortae showing ECs (CD31, green), TAZ (white), and nuclei (Hoechst 33342, blue). Boxed areas shown at higher magnification. Graph showing the percentage of cells in each quartile per mouse (n = 5). (J) Representative images of en face immunofluorescence staining showing ECs (CD31, green), EC nuclei (ERG, white), leukocytes (CD45.2, red), and nuclei (Hoechst 33342, blue) in thoracic aorta, and quantification of CD45+ cells. Mean value per mouse (n = 8–9) was determined by averaging of cells from 9 fields from 3 regions. (K) Circulating white blood cell counts (n = 11–13). Data in A, B, D, and G–K are represented as mean + SD. Statistical analysis was performed by Mann-Whitney test (A and G [ascending aorta]), 2-tailed Student’s t test (B, D, G [descending, abdominal aorta], and H–K), 2-way ANOVA (C), and 2-sided Fisher’s exact test (F). Scale bars: 50 μm. **P < 0.01, ****P < 0.0001. WBC, white blood cells.