Increased absorptive transcytosis and tight junction weakness in heart failure are equally corrected by exercise training and losartan.

Abstract

Reduced ventricular function, renin-angiotensin system upregulation and sympathoexcitation are hallmarks of heart failure (HF). Recently we showed that blood-brain barrier (BBB) lesion within autonomic nuclei contributes to autonomic imbalance and that exercise training (T) normalizes BBB function and improves autonomic control. We sought now to identify the mechanism( involved in both HF-induced lesion and exercise-induced correction. Wistar rats submitted to coronary artery ligation were, after the development of HF, assigned to losartan (Los) or vehicle (Veh) treatments and simultaneously submitted to T or sedentary ( protocol. After hemodynamic/autonomic recordings and evaluation of BBB permeability, brains were harvested for ultrastructural analyses of the barrier (tight junctions (TJ) tightness and vesicles trafficking) within capillaries of the hypothalamic paraventricular nucleus. Local angiotensin II (Ang II) expression and activation of microglial cells (IBA-1 immunofluorescence) were also evaluated. High sympathetic activity and pressure variability, reduced parasympathetic control of the heart, elevated BBB permeability, high vesicular trafficking and TJ weakness exhibited by Veh-rats were equally corrected in Veh-T, Los-and Los-T groups. The increased PVN Ang II expression and IBA-1 density in Veh-group were similarly reduced by T, Los and combination of both. Ang II, colocalized with microglia AT1 receptors, induced their remodeling from disease-associated phenotype in Veh-S rats to homeostatic-surveilling conditions in the other groups. All measured parameters exhibited strong correlations with Ang II availability. Data indicated that changes in PVN Ang II availability induced by HF, exercise and losartan is the key regulator of transcellular and paracellular transport across the BBB.