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

Leila Buttler,Lisete C Michelini,Alexandre Ceroni,Adriana Ruggeri,Matheus G Fragas,Maria T Jordão

doi:10.3389/fphys.2017.01048

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.

Highlights

Chronic hypertension is a major risk factor for coronary artery disease, ischemic and hemorrhagic stroke, congestive heart failure, peripheral vascular, and other diseases (James et al, 2014)
According to our previous studies (Masson et al, 2014, 2015; Chaar et al, 2015) and the present observations showing that training-induced autonomic adaptations as well as improvement of blood-brain barrier (BBB) integrity in the spontaneously hypertensive rats (SHR) occurred after 2 weeks of exercise training, we extended this protocol for 14 experimental days
There are several original observations: (i) BBB disruption is absent in the paraventricular nucleus (PVN), NTS, and RVLM of the SHR at the pre-hypertensive phase, but fully manifested in the established phase of hypertension; (ii) within the PVN there is a progressive increase in BBB dysfunction during the maintained phase of hypertension, an effect not observed in other autonomic nuclei; (iii) exercise training rapidly reverses dye leakage, increases the expression of endothelial barrier antigen and almost normalizes PVN, NTS, and RVLM BBB permeability, an effect strongly correlated with reduced sympathetic vasomotor activity, decreased pressure variability, and increased heart rate variability observed in the trained SHR; (iv) training-induced reduction of brain angiotensin II (Ang II)

Summary

Introduction

Chronic hypertension is a major risk factor for coronary artery disease, ischemic and hemorrhagic stroke, congestive heart failure, peripheral vascular, and other diseases (James et al, 2014). Increased angiotensin II (Ang II) availability activates intracellular pathways and increases neuronal activity within the autonomic areas as the hypothalamic paraventricular nucleus (PVN) and brainstem nuclei (nucleus of the solitary tract, NTS; rostral ventrolateral medulla, RVLM) that have been shown to contribute to neurogenic hypertension (Kang et al, 2009; Shi et al, 2010; Waki et al, 2011; Zubcevic et al, 2011) Both circulating Ang II (via AT1 receptors in endothelial cells) and locally synthetized Ang II cause vascular dysfunction and microglia activation, increase the production of reactive oxygen species, eNOS uncoupling and augment proinflammatory cytokines synthesis, which are important causal factors for sympathoexcitation in neurogenic hypertension (Shi et al, 2010; Waki et al, 2011; Zubcevic et al, 2011). Loss of BBB integrity within the cortex and hippocampus with dysregulation of local perfusion was observed in neurodegenerative diseases including Parkinson and Alzheimer, stroke, traumatic brain injury, and other disorders (Rosenberg, 2012; Erickson and Banks, 2013; Schoknecht et al, 2015)

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