Acute stress activates Piezo1 to drive neutrophil extracellular traps formation and aggravated arterial thrombosis.

BACKGROUND

Acute stress is a critical driver of arterial thrombosis, yet its regulatory mechanisms involving immune cells remain poorly understood. Increasing evidence underscores the interplay between acute stress and inflammation mediated through the neuro-immune axis.

OBJECTIVES

This study aims to elucidate the mechanisms by which acute stress impacts arterial thrombosis, focusing on neutrophil extracellular traps (NETs) and their regulatory pathways.

METHODS

We employed an acute restraint stress model, FeCl3-induced carotid artery thrombosis model, and acute myocardial infarction model to investigate the relationship among NETs, acute stress, and arterial thrombosis. Neutrophils isolated from human peripheral blood and murine bone marrow were used to investigate the mechanisms of NET formation. SYTOX green staining, F-04 staining, immunofluorescence, and co-immunoprecipitation were used to investigate its underlying mechanism.

RESULTS

We found that acute restraint stress triggers NETs formation and promotes thrombosis. In vitro and in vivo experiments revealed that epinephrine induced NETs formation. We further investigate that it is Ca2+ influx, not reactive oxygen species, that mediates epinephrine-induced NETs formation. While administration of ICI-118551, a β2 adrenergic receptor antagonist, inhibited intracellular Ca2+ elevation, suppressed NETs formation, and slowed thrombosis progression. Mechanistic studies revealed that epinephrine induced cytoskeletal remodeling and activated the Piezo1 channel, leading to increased intracellular calcium levels.

CONCLUSION

Our findings demonstrate that acute stress exacerbates arterial thrombosis via epinephrine-induced NETs formation, with the non-selective Ca2+ channel Piezo1 contributing to intracellular calcium elevation. Targeting Piezo1 and NETs may represent novel therapeutic strategies for managing acute cardiovascular events.