A disfunção da barreira hematoencefálica em SHR é normalizada pelo treinamento aeróbio de baixa a moderada intensidade [thesis]

Leila Buttler
AGRADECIMENTOS Agradeço a todas as pessoas que estiveram ao meu lado, acompanhando minhas batalhas e conquistas durante doutorado. Em primeiro lugar agradeço a meus pais, João e Maria, por todo suporte que me deram e sem o qual eu não conseguiria chegar aonde cheguei. Agradeço também a minha irmã Lilian por todo apoio, aos meus sobrinhos Thiago e Fernando que sempre alegram meus dias e ao meu namorado Danilo pelos bons momentos, por todo apoio e compreensão. Agradeço também a professora Lisete
more » ... professora Lisete por ter acreditado em mim e por todo ensinamento concedido desde o mestrado e durante todo o doutorado, contribuindo para meu amadurecimento como pesquisadora. A todas pessoas que passaram pelo Laboratório de Fisiologia Cardiovascular neste período, em especial a Maria Tereza Jordão, amiga e coautora deste trabalho. À técnica do Laboratório de Neuroanatomia Funcional, Aninha, por toda paciência e empenho em me ensinar a técnica de imunoistoquímica. Aos funcionários do biotério de experimentação e às secretarias de pós-graduação e do departamento. Por fim, agradeço as agências de fomento CNPq e FAPESP, sem as quais o trabalho não seria possível. RESUMO BUTTLER, L. A disfunção da barreira hematoencefálica em SHR é normalizada pelo treinamento aeróbio de baixa a moderada intensidade. 2016. 108 f. Tese (Doutorado em Fisiologia Humana) -Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, 2016. Palavras-chave: Hipertensão. Treinamento Aeróbio. Modulação autonômica. Barreira Hematoencefálica. Angiotensina II. ABSTRACT BUTTLER, L. Blood brain barrier dysfunction in SHR is normalized by low to moderate intensity exercise training. 2016. 108 p. Ph. D. thesis (Human Physiology) -Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, 2016. The arterial hypertension (AH) is characterized by autonomic dysfunction and central nervous system alterations leading to the disruption of the blood brain barrier (BBB) and to the development of stroke. The mechanisms by which AH affects BBB function are not completely understood. It is known that angiotensin II (ANGII), via AT1 receptors, has an important role in BBB disruption. Studies from our laboratory showed that aerobic training corrects autonomic dysfunction, being an efficient tool to reduce the expression/activity of the brain renin-angiotensin system. There is no information on possible beneficial effects of training on BBB lesion in hypertensive individuals. In this study we investigated in autonomic areas of spontaneously hypertensive rats (SHR) and normotensive controls (WKY): 1) the time-course changes of BBB lesion since the pre-hypertensive (1 month) up to the establishment of chronic hypertension (3-5 months); 2) the sequential effects (weeks 0, 1, 2 ,4 and 8) of training on functional parameters and their spectral components and on BBB integrity, analyzed by the percent leakage of FITC-dextran, a low molecular weight dye, to the extravascular space (fluorescence microscopy). The expression of endothelial barrier antigen (EBA, a marker of BBB integrity), astrocyte endfeet and microglia (BBB components) and the expression of AT1 receptors in neurons were quantified in the paraventricular nucleus of the hypothalamus (PVN), nucleus of the solitary tract (NTS) and rostroventrolateral medulla (RVLM). SHR and WKY were submitted to aerobic training (T=50 -60 % of maximum capacity, 1 hour/day, 5 days/week) or kept sedentary (S) for 8 weeks. SHR aged 1 month showed intact BBB, but disrupted BBB in the 3 autonomic areas since the 3 rd month of age. Training blocked the progressive increase in arterial pressure (AP) variability observed in the SHR-S; SHR-T showed prompt reduction of sympathetic vasomotor activity (T1-T2) with late increases in heart rate (HR) variability and parasympathetic outflow to the heart, establishment of resting bradycardia and partial AP fall (all these effects significant from T4 on). Training also caused early (T1-T2) and marked reduction of FITC-dextran leakage within the PVN, NTS and RVLM of SHR, normalizing BBB function, as demonstrated by increased EBA expression in these areas. The simultaneous intracerebroventricular infusion of ANGII (or saline) for 2-3 weeks in trained SHR confirmed that the reduction in ANGII availability was crucial to decrease microglia density (and for the maintenance of its inactive state) and to increase the expression of astrocyte endfeet, important BBB constituents whose preservation contribute to the maintenance of BBB integrity. Together our data suggest that the maintenance of BBB integrity in the SHR-T improves tissue perfusion within the PVN, NTS and RVLM, corrects autonomic dysfunction and contributes to the beneficial effect of training even in the persistence of hypertension.
doi:10.11606/t.42.2016.tde-09112016-144856 fatcat:wlxkck26qvcwtlcf6gjlnsr5di