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

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)