Disturbed flow promotes endothelial senescence via a p53-dependent pathway

Area of Science:

• Cardiovascular Biology
• Cellular Senescence
• Atherosclerosis Pathogenesis

Background:

• Atherosclerosis, while linked to systemic factors like high cholesterol, predominantly forms at arterial sites with disturbed blood flow patterns.
• The precise molecular mechanisms connecting disturbed flow-induced mechanical forces to arterial injury remain unclear.
• Endothelial cell (EC) senescence is investigated as a potential link between disturbed flow and arterial injury.

Purpose of the Study:

• To investigate the effects of disturbed and undisturbed blood flow on endothelial cell (EC) senescence.
• To elucidate the molecular pathways involved in flow-induced EC senescence.
• To explore potential therapeutic strategies targeting EC senescence in atherogenesis.

Main Methods:

• LDLR(-/-) mice on a high-fat diet were analyzed for EC senescence markers (β-galactosidase, p53) in aortic ECs.
• In vitro flow systems (orbital shaker, flow bioreactor) were used to expose cultured ECs to different flow conditions.
• Gene silencing (p53, p21) and pharmacological interventions (resveratrol, SRT1720) were employed to study signaling pathways and therapeutic potential.

Main Results:

• High-fat diet induced elevated senescence markers in aortic ECs at disturbed flow sites in mice.
• Disturbed flow in vitro promoted EC senescence via a p53-p21 signaling pathway, while undisturbed flow reduced it.
• Senescent ECs showed reduced migration, impairing arterial repair; Sirtuin 1 activation protected ECs from senescence.

Conclusions:

• Disturbed blood flow induces endothelial senescence through a p53-p21-dependent mechanism.
• Activation of Sirtuin 1 effectively inhibits disturbed flow-induced EC senescence.
• Targeting EC senescence via Sirtuin 1 activation presents a potential strategy for promoting cardiovascular health.