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Effects of heart failure and aerobic training on blood-brain barrier integrity in autonomic brain areas: Mechanisms conditioning the paracellular and transcellular transport.

Grant number: 17/22156-3
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): November 01, 2018
Effective date (End): March 31, 2023
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Lisete Compagno Michelini
Grantee:Hiviny de Ataides Raquel
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:18/14544-6 - Blood-brain barrier: a new paradigm in the treatment of hypertension, AP.TEM


Heart failure (HF) is a syndrome accompanied by sympathoexcitation, robust activation of the renin-angiotensin system (RAS) and marked autonomic dysfunction, which exhibits a very poor prognosis and a high mortality rate. Experimental evidence suggested that blood-brain barrier (BBB) dysfunction compromises brain perfusion and neuronal activity, therefore worsening the sympatho-vagal balance to heart and vessels in several cardiovascular diseases and. It is known that aerobic training (T) is highly effective in reducing both angiotensin II (Ang II) availability and neurohormonal activity in HF patients, as well as in other cardiovascular diseases. It is not known whether autonomic dysfunction in HF is accompanied or not by BBB lesion. It is our working hypothesis that the robust sympathoexcitation in HF is partially determined by BBB dysfunction in brain autonomic areas and that training-induced beneficial effects on autonomic control in HF patients is mediated by normalization of BBB dysfunction within autonomic brain areas as the hypothalamic paraventricular nucleus (PVN), nucleus of the solitary tract (NTS) and rostral ventrolateral medulla (RVLM). Therefore, the objectives of the present study are to investigate in capillaries within brain autonomic areas the effects of HF and T on BBB permeability, identifying possible structural changes in BBB constituents, as well as changes induced in paracellular and transcellular transport across the endothelium. It is our proposal to investigate in the PVN, NTS and RVLM of sedentary (S) and trained HF (coronary descending artery occlusion) and SHAM rats: 1) the presence/absence of BBB lesion (by means of intra-arterial infusion of high and low molecular weight fluorescent dyes); 2) the possible structural changes induced by HF and T on endothelial cells and their tight junctions, on basement membrane, pericytes expression, and morphology of perivascular astrocytes endfeet (immunofluorescence and electron microscopy techniques); 3) the effects of HF and T on paracellular and transcellular transport across the endothelium (electron microscopy). In addition, to confirm the involvement of Ang II on the dysfunction and/or correction of BBB function we will investigate the effects of concomitant Losartan (AT1 receptor antagonist) treatment in subgroups of HF rats during T and S protocols. The possibility to identify the relationship between HF, Ang II availability, BBB functionality and cardiovascular control, as well as the establishment of efficient therapeutic tools to reverse/normalize the deleterious effects of HF, highlights the relevance of the present proposal.

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
RAQUEL, HIVINY DE ATAIDES; PEREGO, SANY M.; MASSON, GUSTAVO S.; JENSEN, LEONARDO; COLQUHOUN, ALISON; MICHELINI, LISETE C.. Blood-brain barrier lesion-a novel determinant of autonomic imbalance in heart failure and the effects of exercise training. Clinical Science, v. 137, n. 15, p. 18-pg., . (18/14544-6, 17/22156-3)
RAQUEL, HIVINY DE ATAIDES; SOUZA GUAZELLI, CARLA FABIANA; VERRI JR, WALDICEU A.; MICHELINI, LISETE C.; MARTINS-PINGE, MARLI CARDOSO. Swimming training reduces iNOS expression, augments the antioxidant defense and reduces sympathetic responsiveness in the rostral ventrolateral medulla of normotensive male rats. Brain Research Bulletin, v. 170, p. 225-233, . (15/24935-4, 17/22156-3)

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