Work

Brain pericytes are an oxidative stress-sensitive cell population damaged through ROS-dependent TRPA1 activation

Year: 2026

Type: preprint

Abstract: Oxidative stress is a pathological process driven by an imbalance between the production and clearance of reactive oxygen species (ROS). It is a hallmark of numerous brain disorders, driving neuroinflammation, blood-brain barrier (BBB) disruption, and neurodegeneration. Here, we used two-photon microscopy in rodent brain slices to evaluate cell-type vulnerability to oxidative stress. We identified a microvascular cell population displaying pronounced sensitivity to H 2 O 2 and thiol oxidation. These Pdgfr-β expressing cells were identified as pericytes and perivascular fibroblasts. Because pericytes regulate capillary perfusion and BBB integrity, we examined mechanisms driving their injury. Pericyte damage was independent of apoptosis or necroptosis, but required Ca 2+ influx. While blocking voltage-gated Ca 2+ , TRPC, Orai channels was ineffective, inhibitors of TRPA1 channels reduced pericyte damage. Immunostaining and western blotting showed TRPA1 associated with brain capillaries and pericytes. Functionally, TRPA1 regulated uptake of the pericyte-selective marker NeuroTrace, whereas pericyte GCaMP6f imaging demonstrated that TRPA1 was not the primary driver of cytosolic Ca 2+ elevations during oxidative stress. These findings establish pericytes as vulnerable targets of oxidative stress and implicate TRPA1 as a mediator of pericyte structural degeneration. This sensitivity to oxidative stress, mediated by ROS-TRPA1 coupling, could contribute to the pericyte stress and degeneration observed in brain pathology.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.10.19.760199