Introduction: Hypertension is increasingly recognized as a neurogenic disorder driven in part by central inflammation. Astrocytes play a critical role in this process by regulating neurovascular coupling and synaptic transmission, functions that are mediated in part by the polarized expression of aquaporin-4 (AQP4). Dysregulation of astrocyte AQP4 localization is associated with impaired cerebral blood flow and altered neuronal excitability during hypertension. Orexin signaling, a potent regulator of sympathetic tone and blood pressure, is implicated in elevated blood pressure when overactive, yet its role in modulating astrocyte function, AQP4 expression, and neurovascular coupling in hypertension formation remains poorly understood. Hypothesis: We hypothesized that orexin signaling mediated by stimulation of orexin 1 receptor (OX1R) may act upstream to influence astrocytic AQP4 expression and polarization. Methods: To test this hypothesis, male Sprague Dawley (SD) rats received bilateral injection of AAV2-OX1R into the paraventricular nucleus (PVN), with AAV-GFP-injected rats served as controls. Blood pressure and heart rate were monitored for 12 weeks using a radio telemetry transducer system. In parallel, astrocytes were isolated from neonatal SD rat brains and transfected with either an AAV-OX1R plasmid to overexpress OX1R or an AAV-OX1R–shRNA plasmid to knock down OX1R expression. Twenty-four hours after transfection, mRNA and protein were extracted from the cells, and AQP4 expression was assessed by real-time PCR and Western blot analysis. Results: PVN AAV2-OX1R-treated rats exhibited mild, but significantly elevated mean arterial pressure (MAP) compared to controls, starting two weeks post-injection and peaking at three weeks (MAP: Control: 99.5±0.9 mmHg vs. AAV2-OX1R: 107.9±1.2 mmHg, n=7~9 per group). These increases persisted until the eighth week when the rats were euthanized. Real-time PCR assay showed that AAV2-OX1R-treated rats exhibited significantly elevated PVN AQP4 mRNA expression compared to controls (1.9-fold, P<0.01). In primary astrocytes, AQP4 mRNA levels increased 3.1-fold following OX1R overexpression, whereas OX1R knockdown significantly reduced AQP4 mRNA levels by 74.4 % compared with untreated control astrocytes (P < 0.01). Conclusion: These findings demonstrate that hyperactive orexin signaling contributes to hypertension, potentially through upregulation of AQP4 expression. Future studies will investigate whether AQP4 inhibition can attenuate orexin system mediated increases in blood pressure. 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.
Simet et al. (2026) studied this question.