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.