Introduction: Cerebrospinal fluid (CSF) is transported within a dedicated peri-vascular network facilitating metabolic waste clearance from the central nervous system. A peri-arterial CSF influx pathway and peri-venous clearance routes are functionally coupled by interstitial bulk flow supported by astrocytic aquaporin 4 water channels, which has recently been termed the “glymphatic system” because of its dependence on glial cells. We recently showed that astrocyte-specific deletion of angiotensin II type 1 receptor improved hymodynamics and prevented left ventricular remodeling with sympathoinhibition in myocardial infarction-induced heart failure rats. We hypothesized that dysfunction of glymphatic system mediated with aquaporin 4 would be associated with sympathoexcitation in hypertension.
Methods and Results: We used 14-16 weeks old stroke-prone spontaneously hypertensive rats (SHRSP) as a model of hypertension with sympathoexcitation. Expression of glial fibrillary acidic protein (cytoskeletal protein of astrocyte) in the brain were significantly lower in SHRSP than in normotensive rats (1.4±0.2 vs. 2.1±0.1 unit, n=5, p<0.05). The expression of aquaporin 4 around blood vessels was significantly lower, and clearance of injected dye from the brain for 1 hour was significantly delayed in SHRSP than in normotensive rats (86±2 vs. 69±4%, n=5, p<0.05). However, these changes were attenuated in SHRSP treated with intracerebroventricular infusion (ICV) of aquaporin 4 activator (p38 MAPK inhibitor) than in normotensive rats. As a result, mean arterial pressure (MAP) and sympathetic nerve activity were significantly lower in SHRSP treated with ICV of aquaporin 4 activator than that with vehicle (MAP; 118±7 vs. 151±9 mmHg, 24 hours urinary norepinephrine excretion; 1.1±0.2 vs. 1.6±0.1 μg/day, n=5 for each, p<0.05 for each). In contrast, ICV of aquaporin 4 inhibitor, TGN-020, to normotensive rats increased MAP with sympathoexcitation.
Conclusions:Glymphatic systemmediated with astrocytic aquaporin 4 is associated with sympathoexcitation in SHRSP. We would like to propose that glymphatic systemmediated with astrocytic aquaporin 4 is potentiated therapeutic target in cardiovascular diseases with abnormal sympathoexcitation.