Pro-inflammatory Vascular Stress in Spontaneously Hypertensive Rats Associated With High Physical Activity Cannot Be Attenuated by Aldosterone Blockade

The effect of high physical activity, performed as voluntary running wheel exercise, on inflammation and vascular adaptation may differ between normotensive and spontaneously hypertensive rats (SHRs). We investigated the effects of running wheel activity on leukocyte mobilization, neutrophil migration into the vascular wall (aorta), and transcriptional adaptation of the vascular wall and compared and combined the effects of high physical activity with that of pharmacological treatment (aldosterone antagonist spironolactone). At the start of the 6th week of life, before hypertension became established in SHRs, rats were provided with a running wheel over a period of 10-months'. To investigate to what extent training-induced changes may underlie a possible regression, controls were also generated by removal of the running wheel for the last 4 months. Aldosterone blockade was achieved upon oral administration of Spironolactone in the corresponding treatment groups for the last 4 months. The number of circulating blood cells was quantified by FACS analysis of peripheral blood. mRNA expression of selected proteins was quantified by RT-PCR. Histology and confocal laser microscopy were used to monitor cell migration. Although voluntary running wheel exercise reduced the number of circulating neutrophils in normotensive rats, it rather increased it in SHRs. Furthermore, running wheel activity in SHRs but not normotensive rats increased the number of natural killer (NK)-cells. Except of the increased expression of plasminogen activator inhibitor (PAI)-1 and reduction of von Willebrand factor (vWF), running wheel activity exerted a different transcriptional response in the vascular tissue of normotensive and hypertensive rats, i.e., lack of reduction of the pro-inflammatory IL-6 in vessels from hypertensive rats. Spironolactone reduced the number of neutrophils; however, in co-presence with high physical activity this effect was blunted. In conclusion, although high physical activity has beneficial effects in normotensive rats, this does not predict similar beneficial effects in the concomitant presence of hypertension and care has to be taken on interactions between pharmacological approaches and high physical activity in hypertensives.

Effects of Voluntary Running Wheel Exercise-Induced Extracellular Vesicles on Anxiety

Anxiety disorders are the most frequently diagnosed psychological condition, associated with serious comorbidities including excessive fear and interference with daily life. Drugs for anxiety disorders are typically prescribed but the side effects include weight gain, nausea, and sleepiness. Exercise is an effective treatment for anxiety. Exercise induces the release of extracellular vesicles (EVs) into the circulation, which transmit signals between organs. However, the effects of exercise-induced EVs on anxiety remain poorly understood. Here, we isolated EVs from the sera of mice that were sedentary or that voluntarily exercised. We characterized the changes in the miRNA profile of serum EVs after 4 weeks of voluntary exercise. miRNA sequencing showed that 82 miRNAs (46 of which were positive and 36 negative regulators) changed after exercise. We selected genes affected by at least two miRNAs. Of these, 27.27% were associated with neurotrophin signaling (9.09% with each of central nervous system neuronal development, cerebral cortical cell migration, and peripheral neuronal development). We also analyzed behavioral changes in mice with 3 weeks of restraint stress-induced anxiety after injection of 20 μg amounts of EVs from exercised or sedentary mice into the left cerebral ventricle. We found that exercise-derived EVs reduced anxiety (compared to a control group) in a nest-building test but found no between-group differences in the rotarod or open field tests. Exercise-derived EVs enhanced the expression of neuroactive ligand-receptor interaction genes. Thus, exercise-derived EVs may exhibit anti-anxiety effects and may be of therapeutic utility.

Increased Energy Expenditure, Lipolysis and Hyperinsulinemia Confer Resistance to Central Obesity and Type 2 Diabetes in Mice Lacking Alpha2α-Adrenoceptors

The alpha2A-adrenoceptors (α2A-ARs) are Gi-coupled receptors, which prejunctionally inhibit the release of norepinephrine (NE) and epinephrine (Epi), and postjunctionally inhibit insulin secretion and lipolysis. We have earlier shown that α2A–/– mice display sympathetic hyperactivity, hyperinsulinemia and improved glucose tolerance. Here we employed α2A–/– mice and placed the mice on a high-fat diet (HFD) to test the hypothesis that lack of α2A-ARs protects from diet-induced obesity and type 2 diabetes (T2D). In addition, a high-caloric diet was combined with running wheel exercise to test the interaction of diet and exercise. HFD was obesogenic in both genotypes, but α2A–/– mice accumulated less visceral fat than the wild-type controls, were protected from T2D, and their insulin secretion was unaltered by the diet. Lack of α2A-ARs is associated with an increased sympatho-adrenal tone, which resulted in increased energy expenditure and fat oxidation rate potentiated by HFD. Fittingly, α2A–/– mice displayed enhanced lipolytic responses to Epi, and increased faecal lipids suggesting altered fat mobilization and absorption. Subcutaneous white fat appeared to be thermogenically more active (measured as Ucp1 mRNA expression) in α2A–/– mice, and brown fat showed an increased response to NE. Exercise was effective in reducing total body adiposity and increasing lean mass in both genotypes, but there was a significant diet-genotype interaction, as even modestly increased physical activity combined with lack of α2A-AR signalling promoted weight loss more efficiently than exercise with normal α2A-AR function. These results suggest that blockade of α2A-ARs may be exploited to reduce visceral fat and to improve insulin secretion.