Abstract 32: Exercise Training Corrects Blood-brain Barrier Dysfunction Within Preautonomic Areas Of Spontaneously Hypertensive Rats By Normalizing The Augmented Transcytosis

Introduction: Besides intense neuro-hormonal activation, hypertension is accompanied by blood-brain barrier (BBB) dysfunction within preautonomic areas and marked autonomic imbalance. We showed previously that exercise training (T) corrected both increased BBB leakage and autonomic dysfunction. There is no information on the mechanism(s) conditioning the normalization of BBB function Hypothesis: We hypothesized that T could modify the transcytosis and/or the paracellular transport across the capillary endothelium Methods: SHR and Wistar rats allocated to T (55% maximal capacity) or sedentary (S) protocols were chronically cannulated for hemodynamic/autonomic recordings and determination of BBB permeability (fluorescent Rhodamine-70kDa+FITC-10kDa dyes given ia ). To analyze hypertension- and T-induced BBB changes, paraventricular hypothalamic nuclei (PVN) was harvested and processed for immunofluorescence and transmission electron microscopy Results: SHR-S vs Wistar-S exhibited augmented SAP and reduced pulse interval (PI) variability, decreased spontaneous baroreflex sensitivity (BrS), increased both PVN BBB leakage (11.4±0.6 vs 3.48 %area) and transcytosis (8.1±1.2 vs 4.8±0.8 vesicles/capillary) but no change in tight junctions’expression (TJ, number/capillary). SHR-T showed a near normal autonomic control, resting bradycardia and a partial AP reduction (-9%) accompanied by normalization of both BBB leakage (3.6±1.5 %area) and transcytosis (3.8±0.7 vesicles/capillary), and increased TJs’ extension (60% occupancy of capillary borders) without changing its expression. Hypertension- and T-induced transcytosis changes were confirmed by caveolin-1 immunofluorescence (SHR-S=139±11, Wistar-S=86±8, SHR-T=81±6 arbitrary units). There were significant correlations between the number of transcytotic vesicles x PVN BBB leakage (Y=1.77x -3.46, r 2 =0.722, P<0.001) and BBB leakage x SAP variability (Y=2.30x +16.6, r 2 =0.246, P<0.001) Conclusions: PVN BBB dysfunction in hypertension is due to increased transcytosis without changes in the paracellular pathway. Training ameliorates SHR’s autonomic control by normalizing transcytosis, with an additional TJs structure improvement

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Possible involvement of oxidative stress as a causative factor in blood–brain barrier dysfunction in stroke-prone spontaneously hypertensive rats

Microvascular Research ◽

10.1016/j.mvr.2013.08.005 ◽

2013 ◽

Vol 90 ◽

pp. 169-172 ◽

Cited By ~ 12

Author(s):

Kumiko Takemori ◽

Tetsuo Murakami ◽

Takashi Kometani ◽

Hiroyuki Ito

Keyword(s):

Oxidative Stress ◽

Blood Brain Barrier ◽

Spontaneously Hypertensive Rats ◽

Causative Factor ◽

Brain Barrier ◽

Hypertensive Rats ◽

Barrier Dysfunction ◽

Spontaneously Hypertensive ◽

Blood Brain

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Abstract 034: Opposite Effects of Hypertension and Training on Blood Brain Barrier Integrity in Autonomic Areas of the Spontaneously Hypertensive Rat

Hypertension ◽

10.1161/hyp.66.suppl_1.034 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Lisete C Michelini ◽

Maria T Jordao ◽

Alexandre Ceroni ◽

Leila Buttler

Keyword(s):

Blood Brain Barrier ◽

Spontaneously Hypertensive Rat ◽

Conscious State ◽

Brain Parenchyma ◽

Brain Barrier ◽

Spontaneously Hypertensive ◽

Area Of Interest ◽

Blood Brain ◽

Spontaneous Baroreflex ◽

Blood Brain Barrier Integrity

It is well known that chronic hypertensive rats exhibit deficient blood brain barrier (BBB). We evaluate age-induced progression of BBB lesion in autonomic areas of the SHR and the possible effect of aerobic training on BBB integrity. SHR aged 1, 3 and 5 month were chronically cannulated for hemodynamic recordings in the conscious state (femoral), followed by anesthesia and dextrans’ infusion (FITC-10kDA + RHO-70kDA, carotid artery). Twenty minutes later rats were sacrificed, brains were removed, post-fixed and cryoprotected. BBB permeability was evaluated in sequential 30 μm slices of the hypothalamic paraventricular nucleus (PVN), nucleus tractus solitarii (NTS) and rostroventrolateral medulla (RVLM) by the capability of FITC10 to leak into the brain parenchyma (in % area/area of interest, fluorescent microscope, ImageJ analysis). Other 3-months old SHR were submitted to treadmill training (T=55% of maximum capacity, 1h/day, 5 d/week) or kept sedentary for 8 weeks. Age-matched WKY served as control. Although SHR aged 1 month were normotensive and exhibited no BBB leakage (0.02±0.01 to 0.15±0.03% in all areas, values similar to WKY), leakage augmented sharply with the establishment of hypertension (average of 8.1±0.7% in SHR-3mo, 9.3±1.2% in SHR-5mo). In the WKY, there was only a small age-induced increase in BBB leakage (average of 0.63±0.05% in PVN, NTS and RVLM). Interestingly T promptly reduced dye leakage in the 3 autonomic areas of the SHR (~1.0±0.2% from 2 up to 8 weeks of training) without changing the leakage in PVN, NTS and RVLM of WKY rats and within the hypoglossus nucleus of the SHR (a non-autonomic area). T-induced improvement of BBB integrity in autonomic areas of the SHR were accompanied by significant reductions of HR (-10%) and MAP (-13%), increased HR variability (+2.1-fold), decreased pressure variability (-49%) and increased spontaneous baroreflex sensitivity (+2.3-fold). Data show that BBB lesion in SHR is caused by the establishment of hypertension and that T improves perfusion of autonomic brain areas in hypertensive individuals by preserving BBB integrity. This adaptive response is crucial for a near normal neuronal activity, thus normalizing autonomic control of the circulation even in the presence of hypertension.

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Maintenance of Blood-Brain Barrier Integrity in Hypertension: A Novel Benefit of Exercise Training for Autonomic Control

Frontiers in Physiology ◽

10.3389/fphys.2017.01048 ◽

2017 ◽

Vol 8 ◽

Cited By ~ 19

Author(s):

Leila Buttler ◽

Maria T. Jordão ◽

Matheus G. Fragas ◽

Adriana Ruggeri ◽

Alexandre Ceroni ◽

...

Keyword(s):

Exercise Training ◽

Blood Brain Barrier ◽

Autonomic Control ◽

Brain Barrier ◽

Barrier Integrity ◽

Blood Brain ◽

Blood Brain Barrier Integrity

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Transcytosis within PVN capillaries - a mechanism determining both hypertension-induced blood-brain barrier dysfunction and exercise-induced correction

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00154.2020 ◽

2021 ◽

Author(s):

Matheus Garcia Fragas ◽

Vanessa Brito Candido ◽

Gustavo Gastão Davanzo ◽

Carla Rocha-Santos ◽

Alexandre Ceroni ◽

...

Keyword(s):

Protein Expression ◽

Blood Brain Barrier ◽

Brain Parenchyma ◽

Autonomic Control ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Caveolin 1 ◽

Blood Brain ◽

Gene And Protein Expression ◽

Exercise Induced

While hypertension disrupts the blood-brain barrier (BBB) integrity within the paraventricular nucleus of hypothalamus (PVN) and increases the leakage into the brain parenchyma, exercise training (T) was shown to correct it. Since there is scarce and contradictory information on the mechanism(s) determining hypertension-induced BBB deficit and nothing is known about T-induced improvement, we sought to evaluate the paracellular and transcellular transport across the BBB within the PVN in both conditions. SHR and WKY submitted to 4-weeks aerobic T or sedentary (S) protocol were chronically catheterized for hemodynamic recordings at rest and intra-arterial administration of dyes (Rhodamine-dextran 70kDa + FITC-dextran 10kDa). Brains were harvesting for FITC leakage examination, qPCR evaluation of different BBB constituents and protein expression of Caveolin-1 and Claudin-5, the main markers of transcytosis and paracellular transport, respectively. Hypertension was characterized by increased arterial pressure and heart rate, augmented sympathetic modulation of heart and vessels, and reduced cardiac parasympathetic control, marked FITC extravasation into the PVN which was accompanied by increased caveolin-1 gene and protein expression, without changes in claudin-5 and others tight junctions' components. SHR-T vs. SHR-S showed a partial pressure reduction, resting bradycardia, improvement of autonomic control of the circulation simultaneously with correction of both FITC leakage and caveolin-1 expression; there was a significant increase in claudin-5 expression. Caveolin-1 content was strongly correlated with improved autonomic control after exercise. Data indicated that within the PVN the transcytosis is the main mechanism governing both hypertension-induced BBB leakage as well as the exercise-induced correction.

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