Aerobic exercise restores blood-brain barrier permeability and astrocyte structure and function within the paraventricular nucleus of the hypothalamus in chronic renovascular hypertension

Introduction: Blood-brain barrier (BBB) disruption in autonomic nuclei, such as the paraventricular nucleus of the hypothalamus (PVN), contributes to sympathetic overactivation in RVH and is driven by alterations in transcellular and paracellular transport, as we have previously shown. Astrocytes play a key role in BBB structure and function, yet their specific contribution to RVH-induced BBB dysfunction remains unclear. We hypothesized that chronic RVH impairs astrocyte structure and function in the PVN, contributing to BBB impairment and autonomic dysregulation, and that aerobic exercise would attenuate these alterations. Methods: RVH was induced using the well-established 2-kidney, 1-clip model. Male Wistar rats underwent placement of a silver clip (ID 0.20 mm) in the left renal artery to produce sustained renal hypoperfusion (or SHAM surgery, no clip placement). Six weeks later, blood pressure was recorded via tail-cuff (RVH: 199 ± 6; SHAM: 137 ± 3 mmHg). From weeks 6-10 after surgery, only RVH rats were assigned to aerobic training (RVH-T: 50–60% maximal capacity, 1 h/day, 5 days/week) or remained sedentary (RVH-S). SHAM rats were kept sedentary (SHAM-S) and served as controls. Ten weeks after surgery, all groups were catheterized for hemodynamic and autonomic recordings. The animals were then subjected to either intra-arterial administration of fluorescent tracers of different molecular weights to quantify BBB permeability or perfused with fixative for immunofluorescence (IF). IF was performed for the astrocytic cytoskeletal marker GFAP, the astrocytic gap-junction protein Connexin-43, and the perivascular astrocyte water channel Aquaporin-4 (AQP-4) within the PVN. Results: RVH-S rats showed marked cardiovascular and autonomic dysfunction versus SHAM-S, including elevated mean arterial pressure (MAP; 188 ± 5 vs. 110 ± 2 mmHg, p< 0.0001) and resting heart rate (HR; 370 ± 9 vs. 336 ± 8 bpm, p=0.0299), increased sympathetic activity (7.20 ± 0.81 vs. 4.81 ± 0.41 mmHg 2 , p=0.0351), and higher systolic blood pressure variability (SBP; 32.21 ± 2.59 vs. 17.52 ± 1.47 mmHg 2 , p< 0.0001). BBB permeability in the PVN was also significantly increased in RVH-S (5.64 ± 0.80 vs. 1.53 ± 0.13% area, p=0.0185). Astrocytic structure and function were markedly impaired in RVH-S compared with SHAM-S, as demonstrated by reduced GFAP expression (18.93 ± 0.91 vs. 31.48 ± 1.18% area, p< 0.0001), decreased Connexin-43 (2.04 ± 0.35 vs. 5.54 ± 0.61% area, p=0.0002), and reduced AQP-4 (47.71 ± 3.00 vs. 100 ± 3.17% area, p< 0.0001). Aerobic training substantially ameliorated key features of hypertension. Relative to RVH-S, trained hypertensive rats (RVH-T) exhibited reductions in MAP (156 ± 7 mmHg, p=0.0030), HR (318 ± 9 bpm, p=0.0006), and restored BBB integrity (1.57 ± 0.11% area, p=0.0189). Training also normalized PVN astrocytic markers in RVH-T: GFAP (26.87 ± 1.96% area, p=0.0021), Connexin-43 (4.72 ± 0.49% area, p=0.0076), and AQP-4 (91.11 ± 3.71% area, p< 0.0001). These improvements were accompanied by reduced sympathetic activity (4.11 ± 0.55 mmHg 2 , p=0.0051) and lower SBP variability (17.02 ± 1.85 mmHg 2 , p< 0.0001). Conclusion: Chronic renovascular hypertension impairs astrocyte structure and function in the PVN, increasing BBB permeability and autonomic dysfunction. Aerobic exercise attenuates these alterations, restoring barrier integrity, astrocytic protein expression, and autonomic control, highlighting astrocytes as one of the mechanisms through which exercise may improve chronic hypertension. Financial support: FAPESP (grants 2018/14544-6; 2022/14337-6 and 2024/21699-7), CNPq (grant 304070/2019-0) and CAPES (grant 88887.388192/2019-00) 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.