Photoaged microplastics disrupt endothelial stretch-sensitive ion channels to impair calcium signaling and vascular...

Plastic-derived micro- and nanoplastics are pervasive, but how environmentally aged particles affect vascular barriers is poorly understood. We hypothesized that photoaged plastics impair endothelial forcesensing, triggering gut-brain-heart barrier failure. Ultraviolet (UV) exposure converted pristine nanoplastics into oxidized, irregular photoaged microplastic aggregates (> 1.2 μm). In human aortic endothelial cells, photoaged particles increased membrane stiffness and activated transcriptional programs linked to permeability, junction disruption, inflammation, and cytoskeletal remodeling. Mechanistically, photoaged particles selectively inhibited Piezo1-mediated Ca²⁺ signaling and downstream Notch activity without changing PIEZO1 expression, and endothelial CRISPR inhibition of PIEZO1 recapitulated these effects. In zebrafish, photoaged plastic exposure increased gut-vascular permeability and systemic spread with brain and heart accumulation, accompanied by reduced neurovascular and myocardial Ca²⁺ signals, depressed cardiac contractility, and abnormal locomotor behavior. Thus, photoaged plastics compromise vascular barriers through disrupted endothelial Piezo1-Notch mechanotransduction.