Agtr1a-expressing pulmonary vagal sensory neurons regulate respiratory output in awake mice

Dysfunctional neural control of breathing complicates bronchopulmonary dysplasia (BPD) via unknown mechanisms. A subpopulation of pulmonary vagal sensory neurons (PSNs) expressing an angiotensin II receptor (Agtr1a+) innervate mechano-, oxygen- and carbon dioxide-sensitive clusters of pulmonary neuroendocrine cells (neuroepithelial bodies; NEBs) located along conducting airways and provide sensory innervation within the nucleus of the solitary tract. Accordingly, Agtr1a+ PSNs are positioned to modulate breathing, and this sensory pathway may be disrupted in BPD, where NEB hyperplasia is a common pathological feature. However, the functional role of Agtr1a+ PSNs in health and BPD remains unknown. Here, we tested the hypothesis that Agtr1a+ PSN activation would differentially influence respiratory output in awake healthy and BPD mice. To test this hypothesis, Agtr1aCre+ and Cre- mouse pups with nursing dam were exposed to 70% O 2 (70HX; Cre+ n=2, Cre- n=8) or 90% O 2 (90HX; Cre+ n=4, Cre- n=2) for the first 5 days of life to induce a mild or severe BPD phenotype (controls remained in normoxic air (NX; Cre+ n=13, Cre- n=16)). At postnatal (P) days 5-11, all mice were intratracheally treated with a Cre-dependent retrograde adeno-associated virus (AAV) to drive Cre-dependent expression of an excitatory synthetic receptor (Gq-DREADD) in Agtr1a+ PSNs. Three weeks later, room air and hypoxic (12% O 2 ) breathing were measured by whole-body plethysmography before and after DREADD activation via intraperitoneal injection of the synthetic ligand, deschloroclozapine (DCZ). Following functional studies, ganglia were collected and Gq specificity was confirmed within Agtr1a+ PSNs via RNAscope. Minute ventilation (mL/min/100g) before DCZ was no different between NX, 70HX, or 90HX mice (p=0.5296). Also, DCZ appropriately had no effects in all Agtr1aCre- mice (all p >0.1460). However, in NX Agtr1aCre+ mice, DCZ elicited lower tidal volume (mL/breath/100g) during room air (p=0.004) and hypoxia (p=0.0345) and lower minute ventilation during room air (p=0.0003) when compared to NX Agtr1aCre- mice. We observed no differences between NX Agtr1aCre+ and Cre- mice in the post-DCZ hypoxic ventilatory response (p=0.4124). Together, these data suggest that Agtr1a+ PSNs act as a modulatory afferent pathway that constrains baseline ventilatory output while preserving hypoxia-evoked respiratory drive in healthy mice. Unlike our NX mice, 90HX Agtr1aCre+ mice showed no detectable effect for either tidal volume or minute ventilation under normoxic (tidal volume p=0.1897, minute ventilation p=0.9710) or hypoxic conditions (tidal volume p=0.4737, minute ventilation p=0.9362); suggesting that BPD disrupts the Agtr1a+ PSN neuromodulation of breathing observed in healthy mice. Ongoing studies continue to measure the impact of Agtr1a+ PSN stimulation and inhibition on breathing and metabolic rate in healthy and BPD mice. 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.