Endothelial progerin expression causes cardiovascular pathology through an impaired mechanoresponse
Selma Osmanagic-Myers, … , Maria Eriksson, Roland Foisner
Selma Osmanagic-Myers, … , Maria Eriksson, Roland Foisner
Published November 13, 2018
Citation Information: J Clin Invest. 2019;129(2):531-545. https://doi.org/10.1172/JCI121297.
View: Text | PDF
Research Article Aging Cell biology Article has an altmetric score of 34

Endothelial progerin expression causes cardiovascular pathology through an impaired mechanoresponse

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder characterized by accelerated cardiovascular disease with extensive fibrosis. It is caused by a mutation in LMNA leading to expression of truncated prelamin A (progerin) in the nucleus. To investigate the contribution of the endothelium to cardiovascular HGPS pathology, we generated an endothelium-specific HGPS mouse model with selective endothelial progerin expression. Transgenic mice develop interstitial myocardial and perivascular fibrosis and left ventricular hypertrophy associated with diastolic dysfunction and premature death. Endothelial cells show impaired shear stress response and reduced levels of endothelial nitric oxide synthase (eNOS) and NO. On the molecular level, progerin impairs nucleocytoskeletal coupling in endothelial cells through changes in mechanoresponsive components at the nuclear envelope, increased F-actin/G-actin ratios, and deregulation of mechanoresponsive myocardin-related transcription factor-A (MRTFA). MRTFA binds to the Nos3 promoter and reduces eNOS expression, thereby mediating a profibrotic paracrine response in fibroblasts. MRTFA inhibition rescues eNOS levels and ameliorates the profibrotic effect of endothelial cells in vitro. Although this murine model lacks the key anatomical feature of vascular smooth muscle cell loss seen in HGPS patients, our data show that progerin-induced impairment of mechanosignaling in endothelial cells contributes to excessive fibrosis and cardiovascular disease in HGPS patients.

Authors

Selma Osmanagic-Myers, Attila Kiss, Christina Manakanatas, Ouafa Hamza, Franziska Sedlmayer, Petra L. Szabo, Irmgard Fischer, Petra Fichtinger, Bruno K. Podesser, Maria Eriksson, Roland Foisner

×

Figure 5

Impaired mechanical response in Prog-Tg mice.

Options: View larger image (or click on image) Download as PowerPoint
Impaired mechanical response in Prog-Tg mice. (A) En face view of the en...
(A) En face view of the endothelial layer in the area of descending aorta isolated from Wt and Prog-Tg mice and stained with indicated antibodies and Hoechst (DNA) dye. Arrows indicate cells with high progerin levels showing misalignment within aortic sheet (images are representative of n = 4 Wt and Prog-Tg littermate pairs). Scale bar: 10 μm. (B) Box plots showing cell aspect ratio and alignment angle (angle between cell major axis and line perpendicular to flow direction) analyzed in equivalent descending aorta regions of Wt and Prog-Tg littermate pairs (n > 400 cells per genotype). ***P < 0.001 by Mann-Whitney U test. (C) ECs cultured in flow channels before and after exposure to flow of medium (12 dyn/cm2) for 3 hours were processed for immunofluorescence microscopy using antibodies and DAPI dye as indicated (images are representative of n = 3 independent experiments). Arrow indicates flow direction. Scale bars: 10 μm. (D) Box plots showing cell aspect ratios analyzed in Wt and Prog-Tg ECs after 0-hour (0h) and 3-hour (3h) flow exposure (n > 150 cells per condition and per genotype). One-way ANOVA with Dunn’s multiple comparisons test revealed **P < 0.01 (Wt 0h versus Wt 3h), ***P < 0.001 (Wt 3h versus Prog-Tg 3h), and not significant (NS, Prog-Tg 0h versus 3h and all other comparisons). Right panel, proportion of cells with aligned actin stress fibers in ECs after 3 hours of shear stress exposure. Stress fibers were considered aligned if their direction was parallel to or within 30° to the cell major axis, and misaligned if not (n = 4; >250 cells per genotype). ***P < 0.001 by Mann-Whitney U test. (B and D) Data presented as median (middle line) with boxes encompassing 25th to 75th percentile, and whiskers, minimum to maximum values.