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The role of microglia in modulating the deleterious effects of hypertension on Blood-Brain Barrier (BBB) permeability: the benefits of the aerobic exercise training

Grant number: 19/23660-2
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): April 01, 2020
Effective date (End): March 31, 2022
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Vagner Roberto Antunes
Grantee:Izabela Martina Ramos Ribeiro de Toledo
Home 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

Abstract

Hypertension is characterized by hyperactivation of the cerebral renin-angiotensin (SARS) system, increased oxidative stress and local inflammation, which determine impaired reflex control, autonomic dysfunction and sympathetic overactivity with consequent deleterious effects to the cardiovascular system. Recently, it has been described that the deleterious effects of hypertension could also be determined by an impairment of the cerebral circulation due to BBB damage in the brain autonomic areas. In recent study we have observed that aerobic training is effective to reduce and correcting the permeability of the BBB, in a time-course simultaneous to the normalization of the autonomic control of the cardiovascular system (Buttler et al., 2017). However, we do not know the mechanism(s) by which hypertension and aerobic exercise training affect the function of the BBB. It has been shown that microglia (CNS resident macrophages) is an important source of proinflammatory cytokines, which is activated in hypertension, but switches to its inactive state in trained hypertensive patients. Our working hypothesis resides in the fact that microglia could release neurotrophic factors that contributes to BBB dysfunction and modulate neuronal function, leading to hypertension. In addition, we presume that may exercise training may facilitate the reduction of BBB permeability by affect the factor being synthetized and released by microglia. The aims of the project are: 1) to evaluate in a mice model of Ang II-induced hypertension the effects of exercise training on the autonomic function and the permeability of the BBB; 2) to identify the soluble and neurotrophic factors released by microglia in the PVN, NTS and RVLM; 3) to block the releasing factors of microglia in sedentary and trained hypertensive mice to evaluate their effects on the autonomic control and permeability of the BBB; 3) to validate, in sedentary and trained SHR and in a renovascular hypertension model (2K1C), the effects of microglial factors released by hypertension and before and after aerobic training on the integrative of the BBB. (AU)