Blood-brain barrier: a new paradigm in the treatment of hypertension

• Grant number: 18/14544-6
• Support Opportunities: Research Projects - Thematic Grants
• Start date: June 01, 2019
• End date: December 31, 2024
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Lisete Compagno Michelini
• Grantee: Lisete Compagno Michelini
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Pesquisadores principais: Alison Colquhoun ; Vagner Roberto Antunes
• Associated researchers: Gustavo Santos Masson ; Joseph Francis ; Song T. Yao
• Associated scholarship(s): 24/14514-0 - Microglia in the modulation of blood-brain barrier functionality during the onset of spontaneous hypertension, BP.DD; 23/03054-6 - Modulation of blood-brain barrier permeability by microglia during the transition from pre- to hypertensive phase in spontaneously hypertensive rats, BP.DD; 22/14337-6 - Effects of renovascular hypertension and physical training on permeability and on ultrastructural changes in the blood-brain barrier., BP.DR; + associated scholarships 22/07465-8 - The role of microglia in modulating the deleterious effects of hypertension on Blood-Brain Barrier (BBB) permeability: the benefits of the aerobic exercise training, BP.PD; 21/12498-0 - Angiotensin II (Ang II) and microglia modulate blood-brain barrier permeability in Hypertension: beneficial effects of exercise training, BP.PD; 19/23660-2 - The role of microglia in modulating the deleterious effects of hypertension on Blood-Brain Barrier (BBB) permeability: the benefits of the aerobic exercise training, BP.PD; 19/26620-1 - Training of Undergraduate Students in Research Techniques in Cardiovascular Physiology and Effort., BP.TT; 17/22156-3 - Effects of heart failure and aerobic training on blood-brain barrier integrity in autonomic brain areas: Mechanisms conditioning the paracellular and transcellular transport., BP.PD - associated scholarships

Abstract

Autonomic dysfunction and the consequent activation of the renin-angiotensin system are the main determinants of the deleterious effects of hypertension. Increased availability of angiotensin II (Ang II) within brain autonomic areas activates intracellular signaling pathways thus augmenting neuronal activity and resulting in sympathoexcitation that characterizes the neurogenic hypertension. Besides the effects of locally synthetized and circulating Ang II (which acts through receptors located in brain vessels), Stern and cols. recently identified blood-brain barrier (BBB) lesion in autonomic areas of hypertensive rats allowing plasma Ang II access into these areas, a mechanism that potentiates its deleterious effects. Since in our research line we pursue the identification and the correction of brain mechanisms conditioning the autonomic dysfunction in hypertension, we evaluated the relationship between BBB and autonomic control. In the SHR (best experimental model of primary or neurogenic hypertension), we observed that: i) BBB dysfunction and autonomic imbalance were absent in the pre-hypertensive phase, but fully manifested in the chronic phase, ii) aerobic training starting in the chronic phase was effective in correcting both BBB and autonomic dysfunctions, iii) these effects were abrogated by simultaneous intracerebroventricular infusion of Ang II (Buttler et al, 2017). In the literature, there is no information on the mechanisms by which hypertension and/or Ang II damage BBB function and nothing is known on the potentiality of aerobic training in correcting BBB dysfunction. To uncover these mechanisms are the main goals of this project. The BBB is a selective barrier between the systemic circulation and the central nervous system formed by a complex cellular system including endothelial cells (closely joined by tight junctions that block the paracellular allowing only the transcellular transport), basement membrane, pericytes and astrocytes endfeet (that enveloped brain capillaries). The microglia, besides not being a structural component, participates in BBB function by locally releasing pro-inflammatory cytokines mainly in hypertensive states. It is our working hypothesis that hypertension and/or Ang II disrupt the BBB while aerobic training corrects its dysfunction by altering the expression of one or more BBB constituents or their inter-relation and/or by changing the transport mechanisms between plasma and brain parenchyma. Therefore, our objectives are to evaluate within autonomic areas (paraventricular nucleus of the hypothalamus, nucleus of the solitary tract, rostroventrolateral medulla) of the SHR and respective controls the effects of increased blood pressure, Ang II availability and aerobic training on: 1) BBB permeability, 2) gene and protein expression of BBB constituents, 3) the structure and ultrastructure of BBB, 4) transcellular and paracellular transports across the BBB, 5) on the simultaneous autonomic control of the circulation. Also to uncover whether training-induced changes are specific for the SHR or generalized in hypertension, we will analyze the BBB permeability, expression/function of BBB constituents and endothelial transport mechanisms in a secondary model of hypertension - the renovascular 2 Kidney- 1 Clip. Importantly, these studies will uncover the role of BBB function for an adequate perfusion of the central nervous system, the consequences determined by chronic hypertension, besides giving clues on appropriate therapeutic tools to improve/reverse their deleterious effects on cardiovascular control. (AU)

Scientific publications

(9)

(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 A.; MANICA, LOUISI A.; CERONI, ALEXANDRE; MICHELINI, LISETE C.. Exercise training improves cardiovascular control in sinoaortic denervated SHR by reducing the elevated angiotensin II and augmenting angiotensin-(1-7) availability within autonomic and neuroendocrine PVN nuclei. Peptides, v. 153, p. 7-pg., 2022-07-01. (17/22156-3, 18/14544-6, 18/12280-1)

FRAGAS, MATHEUS GARCIA; CANDIDO, VANESSA BRITO; DAVANZO, GUSTAVO GASTAO; ROCHA-SANTOS, CARLA; CERONI, ALEXANDRE; MICHELINI, LISETE C.. Transcytosis within PVN capillaries: a mechanism determining both hypertension-induced blood-brain barrier dysfunction and exercise-induced correction. AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, v. 321, n. 5, p. R732-R741, NOV 2021. (18/14544-6)

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., 2023-08-01. (18/14544-6, 17/22156-3)

GOMES, PAULA; PEREGO, SANY; MICHELINI, LISETE; ANTUNES, VAGNER. Aerobic training reduces microglial activation and TNFa release in the hypothalamus of hypertensive rats. PHYSIOLOGY, v. 39, p. 2-pg., 2024-05-01. (18/14544-6, 22/07465-8)

CANDIDO, VANESSA B.; PEREGO, SANY M.; CERONI, ALEXANDRE; METZGER, MARTIN; COLQUHOUN, ALISON; MICHELINI, LISETE C.. Trained hypertensive rats exhibit decreased transcellular vesicle trafficking, increased tight junctions' density, restored blood-brain barrier permeability and normalized autonomic control of the circulation. FRONTIERS IN PHYSIOLOGY, v. 14, p. 14-pg., 2023-02-23. (18/14544-6)

GONCALVES, LIVIA DE SOUZA; SALES, LUCAS PEIXOTO; SAITO, TIEMI RAQUEL; CAMPOS, JULIANE CRUZ; FERNANDES, ALAN LINS; NATALI, JOSE; JENSEN, LEONARDO; ARNOLD, ALEXANDRE; RAMALHO, LISLEY; BECHARA, LUIZ ROBERTO GRASSMANN; et al. Histidine dipeptides are key regulators of excitation-contraction coupling in cardiac muscle: Evidence from a novel CARNS1 knockout rat model. REDOX BIOLOGY, v. 44, AUG 2021. (17/16540-5, 13/14746-4, 17/11142-1, 13/07937-8, 17/13552-2, 19/24899-9, 18/14544-6, 19/25032-9, 14/11948-8, 20/04006-7)

PEREGO, SANY M.; RAQUEL, HIVINY A.; CANDIDO, VANESSA B.; MASSON, GUSTAVO S.; MARTINS, MARIANA M.; CERONI, ALEXANDRE; MICHELINI, LISETE C.. Hypertension depresses but exercise training restores both Mfsd2a expression and blood-brain barrier function within PVN capillaries. AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, v. 325, n. 3, p. 9-pg., 2023-09-17. (18/14544-6)

FABRICIO, MAYARA F.; JORDAO, MARIA T.; MIOTTO, DANYELLE S.; RUIZ, THALLES F. R.; VICENTINI, CARLOS A.; LACCHINI, SILVIA; SANTOS, CARLOS FERREIRA; MICHELINI, LISETE C.; AMARAL, SANDRA L.. Standardization of a new non-invasive device for assessment of arterial stiffness in rats: Correlation with age-related arteries' structure. METHODSX, v. 7, 2020. (18/14544-6, 14/23229-6, 15/03965-2, 17/00509-1)

DELLACQUA, LAIS OLIVEIRA; GOMES, PAULA MAGALHAES; BATISTA, JULIA SANTOS; MICHELINI, LISETE COMPAGNO; ANTUNES, VAGNER ROBERTO. Exercise-induced neuroplasticity in autonomic nuclei restores the cardiac vagal tone and baroreflex dysfunction in aged hypertensive rats. Journal of Applied Physiology, v. 136, n. 1, p. 10-pg., 2024-01-07. (12/22368-7, 22/07465-8, 13/06206-0, 18/14544-6, 11/51410-9)