PNA5, a novel Mas receptor agonist, restores neurovascular function in 5x-FAD mice

Cerebral microvascular dysfunction contributes to AD progression and severity, including impaired neurovascular coupling (NVC). We recently showed that, in the 5x-FAD model of AD, NVC impairment is a consequence of decreased activity of the large-conductance, Ca 2+ -activated K + channel (BKCa), caused by the pro-inflammatory and oxidative environment of the AD vasculature. PNA5, a Mas receptor agonist, has antioxidant and anti-inflammatory properties, and we recently showed that PNA5 improves NVC in a model of vascular contributions to cognitive impairment and dementia. However, the potential beneficial effects of PNA5 in the cerebral vasculature remain unknown. Therefore, we hypothesized that PNA5 will restore vascular BKCa function and NVC via reduced BKCa nitro-oxidation in 5x-FAD. To test this hypothesis, we treated five-month-old male and female 5x-FAD mice with PNA5 (100 µg/kg/day, s.c.) or saline (vehicle) for one month. Using inside-out patch clamp electrophysiology to record single channel BKCa currents in cerebral artery smooth muscle cells (SMC), we observed restored BKCa activity in 5x-FAD+PNA5 compared to 5x-FAD+vehicle. Incubation of patches with dithiothreitol (DTT), a reducing agent, did not further increase BKCa currents, suggesting that PNA5 reduced channel oxidation. Further, BKCa-dependent vasoreactivity of isolated cerebral arteries, recorded as a constriction after exposure to the BKCa inhibitor iberiotoxin, was similarly improved in 5x-FAD+PNA5 when compared to vehicle-treated mice, without additive effects of DTT. PNA5 treatment significantly improved NVC in 5x-FAD mice, observed as a large increase in cerebral perfusion following whisker stimulation. Executive function, assessed by the nest building test, remained stable in 5x-FAD+PNA5, whereas it progressively declined in 5x-FAD+vehicle. Contrary to our hypothesis, BKCa nitro-oxidation was not reduced by PNA5, suggesting that other oxidative mechanisms may also play a role in SMC BKCa dysfunction. Together, these data suggest that PNA5 improves cerebral neurovascular function by restoring BKCa activity, although the mechanism is independent of nitro-oxidation. NIA R01 AG073230 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.