Abstract
Background and Objective: The CNS possesses the astrocyte-dependent perivascular glymphatic pathway to facilitate CSF-ISF exchange and clearance of interstitial wastes. Cerebral arterial pulsations drive glymphatic flow, and cerebrovascular pulsatility is dependent, at least in part, on systemic blood pressure. Renin-angiotensin-aldosterone axis dysregulation is responsible for hypertension, a condition that affects nearly 30% of the US population and 40% of individuals globally. Here, we investigate how manipulation of the RAA axis, both with angiotensin and common anti-hypertensive pharmacotherapy, influences glymphatic flow. Methods: All drugs were administered to the cisterna magna via cannulation at a rate of 1 μL/min for a total volume of 5 μL. Immediately after, 1% AlexaFluor-555 conjugated bovine serum albumin (BSA-555) was delivered intracisternally at a rate of 2 μL/min for a total volume of 10 μL. 30 minutes following tracer injection, cerebral tissues were collected and processed for ex vivo conventional fluorescence microscopy. Tissue area occupied by fluorophore was quantified, with greater percent areas indicating increased glymphatic influx. Results: Pre-treatment with Angiotensin II (ATII, 1 μM) increased glymphatic influx relative to vehicle-injected controls. Losartan (1 μM), an AT1 receptor inhibitor, was found to decrease glymphatic CSF influx, indicating that ATII acts through the AT1 receptor to increase glymphatic flow. Systemic administration of DSP-4 (50 mg/kg), a neurotoxin known to deplete locus coeruleus norepinephrine, resulted in suppressed glymphatic influx. Co-administration of ATII in DSP-4 treated mice or in mice receiving a norepinephrine inhibitory cocktail (1 μM) resulted in decreased glymphatic influx, suggesting that ATII regulates glymphatic pathway function through a NE-dependent mechanism. Conclusions: Angiotensin II acts via the AT1 receptor to increase glymphatic influx in a norepinephrine-dependent manner. Further study on hemodynamic regulation of glymphatic flow may reveal mechanisms of hypertension-related brain pathology.
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