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

Abstract

The blood-brain barrier (BBB) is a complex multicellular structure acting as selective barrier controlling the transport of substances between these compartments. Accumulating evidence has shown that chronic hypertension is accompanied by BBB dysfunction, deficient local perfusion and plasma angiotensin II (Ang II) access into the parenchyma of brain areas related to autonomic circulatory control. Knowing that spontaneously hypertensive rats (SHR) exhibit deficient autonomic control and brain Ang II hyperactivity and that exercise training is highly effective in correcting both, we hypothesized that training, by reducing Ang II content, could improve BBB function within autonomic brain areas of the SHR. After confirming the absence of BBB lesion in the pre-hypertensive SHR, but marked fluorescein isothiocyanate dextran (FITC, 10 kD) leakage into the brain parenchyma of the hypothalamic paraventricular nucleus (PVN), nucleus of the solitary tract, and rostral ventrolateral medulla during the established phase of hypertension, adult SHR, and age-matched WKY were submitted to a treadmill training (T) or kept sedentary (S) for 8 weeks. The robust FITC leakage within autonomic areas of the SHR-S was largely reduced and almost normalized since the 2nd week of training (T2). BBB leakage reduction occurred simultaneously and showed strong correlations with both decreased LF/HF ratio to the heart and reduced vasomotor sympathetic activity (power spectral analysis), these effects preceding the appearance of resting bradycardia (T4) and partial pressure fall (T8). In other groups of SHR-T simultaneously infused with icv Ang II or saline (osmotic mini-pumps connected to a lateral ventricle cannula) we proved that decreased local availability of this peptide and reduced microglia activation (IBA1 staining) are crucial mechanisms conditioning the restoration of BBB integrity. Our data also revealed that Ang II-induced BBB lesion was faster within the PVN (T2), suggesting the prominent role of this nucleus in driven hypertension-induced deficits. These original set of data suggest that reduced local Ang II content (and decreased activation of its downstream pathways) is an essential and early-activated mechanism to maintain BBB integrity in trained SHR and uncovers a novel beneficial effect of exercise training to improve autonomic control even in the presence of hypertension.

Cutaneous inflammation differentially regulates the expression and function of Angiotensin‐II types 1 and 2 receptors in rat primary sensory neurons

“…We chose this antibody because of concerns about the selectivity of other commercially available antibodies against AT2R (Hafko et al ). A polyclonal rabbit anti‐AT1R (Santa Cruz Biotechnology Cat# sc‐579, , 1 : 200) was used (Buttler et al ). We performed a further characterization of these antibodies comparing them against two other commercially available anti‐AT2R antibodies (Figure S1).…”

Pharmacological depletion of microglia prevents vascular cognitive impairment in Ang II-induced hypertension

“…In addition, the depletion of microglia, and partially PVMs as achieved in our study, did not lead to a blood pressure reduction. The contribution of both macrophage subsets in the modulation of the autonomic activity in cardiovascular regulatory centers is well known [35,[57][58][59][60][61]. Previous studies reported that Ang II was able to increase blood pressure via the activation of microglia due to a lower BBB permeability in the paraventricular nucleus of the hypothalamus (PVN) in hypertensive animals [57,62].…”

Paravascular spaces: entry to or exit from the brain?

“…It is possible that the BBB dysfunction is very subtle in hypertensive rats, initially affecting ions and water only. Overt leakiness might be present only in specific areas, including the paraventricular nucleus and brainstem (Biancardi, Son, Ahmadi, Filosa, & Stern, 2014;Buttler et al, 2017;Setiadi, Korim, Elsaafien, & Yao, 2018). Nonetheless, there is a remarkable similarity between sites of tracer accumulation and sites of amyloid-deposition in rodents (Bedussi, Naessens, et al, 2017).…”