Hypertension depresses but exercise training restores both Mfsd2a expression and blood-brain barrier function within PVN capillaries

Abstract

Hypertension augments while exercise training corrects the increased vesicle trafficking (transcytosis) across the blood-brain barrier (BBB) within preautonomic areas and the autonomic imbalance. There is no information on a possible mechanism(s) conditioning these effects. Knowing that Mfsd2a is the major transporter of docosahexaenoic acid (DHA) and that Mfsd2a knockout mice exhibited leaky BBB, we sought to identify its possible involvement in hypertension- and exercise-induced transcytosis across the BBB. Spontaneously hypertensive rats (SHR) and Wistar rats were submitted to treadmill training (T) or kept sedentary (S) for 4 wk. Resting hemodynamic/autonomic parameters were recorded in conscious chronically cannulated rats. BBB permeability within the hypothalamic paraventricular nucleus (PVN) was evaluated in anesthetized rats. Brains were harvested for Mfsd2a and caveolin-1 (an essential protein for vesicle formation) expression. SHR-S versus Wistar-S exhibited elevated arterial pressure (AP) and heart rate (HR), increased vasomotor sympathetic activity, reduced cardiac parasympathetic activity, greater pressure variability, reduced HR variability, and depressed baroreflex control. SHR-S also showed increased BBB permeability, reduced Mfsd2a, and increased caveolin-1 expression. SHR-T versus SHR-S exhibited increased Mfsd2a density, reduced caveolin-1 protein expression, and normalized PVN BBB permeability, which were accompanied by resting bradycardia, partial AP drop, reduced sympathetic and normalized cardiac parasympathetic activity, increased HR variability, and reduced pressure variability. No changes were observed in Wistar-T versus Wistar-S. Training is an efficient tool to rescue Mfsd2a expression, which by transporting DHA into the endothelial cell reduces caveolin-1 availability and vesicles' formation. Exercise-induced Mfsd2a normalization is an important mechanism to correct both BBB function and autonomic control in hypertensive subjects.

Keywords: autonomic control; blood-brain barrier; caveolin-1; exercise training; major facilitator superfamily domain containing 2a.