Altered transport mechanisms across the blood-brain barrier in renovascular hypertension: Effects of exercise training

Introduction: We showed previously in SHR that increased blood-brain barrier (BBB) permeability within autonomic areas contributed to autonomic imbalance. Dysfunctional BBB was due to elevated transcytosis, with unaltered both tight junctions and paracellular transport. These alterations were reversed by aerobic training. Renovascular hypertensive rats also exhibited dysfunctional BBB, but the transport mechanism(s) underlying barrier permeability were not known. Objective: To evaluate hemodynamic/autonomic control of the circulation, BBB permeability and transport mechanisms across the barrier within the paraventricular hypothalamic nucleus (PVN) of sedentary and trained renal hypertensive rats. Methods: Male Wistar rats were subjected to the implantation of a silver clip (ID: 0.20 mm) on the left renal artery to induce renovascular hypertension (2 kidney-1 clip, 2K1C) or a sham surgery (SHAM). Six weeks’ post-surgery (tail-cuff pressure: 2K1C=199±6 mmHg, SHAM=137±3 mmHg), they were assigned to either aerobic training (T = 50–60% maximum capacity, 1 h/day, 5 days/week) or remained sedentary (S) for 4 weeks. Rats were chronically cannulated for hemodynamic/autonomic recordings and BBB permeability measurement (high± low-molecular-weight fluorescent dyes given i.a.). Brains were harvested for PVN caveolin-1 (transcytosis marker) and claudin-5 (tight junction protein regulating paracellular transport) immunofluorescence. Ethical approval: CEUA 3112251119/6194060324. Results: 2K1C-S vs SHAM-S group exhibited high MAP and resting HR (179±7 vs. 110±2 mmHg; 370±9 vs. 336±8 bpm), increased sympathetic activity (7.18±2.55 vs. 3.73±0.38 mmHg 2 ), reduced baroreflex sensitivity (BrS, 0.68±0.12 vs. 1.03±0.05 ms/mmHg), and elevated SAP variability (31.36±7.34 vs. 13.03±1.75 mmHg 2 ). 2K1C-S also exhibited elevated BBB permeability (4.64±0.19 vs. 0.54±0.08% area), increased caveolin-1 (148±2 vs. 107±1 AU), and reduced claudin-5 (4.04±0.41 vs. 23.50±1.53 AU) in the PVN. Compared to 2K1C-S, 2K1C-T had lower MAP (-12%) and HR (-14%), normalized BBB permeability (0.46±0.11%), caveolin-1 (103±2 AU) and claudin-5 (21.78±0.5 AU) expression. These responses were accompanied by reduced sympathetic activity (3.41±0.61 mmHg 2 ), BrS (0.86±0.18 ms/mmHg) and SBP variability (16.02±2.82 mmHg 2 ), No changes were observed in SHAM-T vs. SHAM-S. Conclusion: Similar to spontaneous hypertension, BBB permeability in secondary hypertension is associated with significant increase in transcellular transport, but shows tight junctions’ weakness and impaired paracellular transport due to a sharp reduction in claudin-5 expression, which is not observed in SHR. Aerobic training also restores BBB functionality in renovascular hypertension, contributing to normalize sympathetic hyperactivity and correct the autonomic dysfunction, thus reducing the elevated blood pressure variability seen in renovascular hypertension. Financial support: FAPESP (grants 2018/14544-6 and 2022/14337-6); CNPq (grant 304070/2019-0) and CAPES (grant 88887.388192/2019-00) This abstract was presented at the American Physiology Summit 2025 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.