Endothelial progerin expression causes cardiovascular pathology through an impaired mechanoresponse

Area of Science:

• Cardiovascular Biology
• Cellular Mechanobiology
• Genetics of Aging

Background:

• Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder causing rapid premature aging and severe cardiovascular complications, primarily extensive fibrosis.
• The underlying cause is a mutation in the LMNA gene, resulting in the production of a truncated protein called progerin, which accumulates in the cell nucleus.

Purpose of the Study:

• To investigate the specific role of endothelial cells in the cardiovascular pathology of HGPS.
• To elucidate the molecular mechanisms by which progerin in endothelial cells contributes to fibrosis and cardiac dysfunction.

Main Methods:

• Generation of an endothelium-specific HGPS mouse model with targeted progerin expression in endothelial cells.
• Analysis of cardiac structure, function, and fibrosis in transgenic mice.
• Molecular investigation of endothelial cell mechanosignaling pathways, including shear stress response, nitric oxide synthase (eNOS) levels, and mechanoresponsive transcription factors.

Main Results:

• Endothelium-specific progerin expression induced myocardial and perivascular fibrosis, left ventricular hypertrophy, and diastolic dysfunction, leading to premature death in mice.
• Endothelial cells exhibited impaired response to shear stress, reduced eNOS and nitric oxide (NO) levels, and disrupted nucleocytoskeletal coupling.
• Progerin dysregulated the mechanoresponsive transcription factor MRTFA, which directly reduced eNOS expression and promoted a profibrotic paracrine signaling in fibroblasts.

Conclusions:

• Progerin-induced defects in endothelial mechanosignaling contribute significantly to the fibrosis and cardiovascular disease observed in HGPS.
• Targeting MRTFA-mediated pathways may offer a therapeutic strategy to ameliorate progerin-induced cardiovascular pathology.