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Adaptations on perivascular innervation and remodeling in resistance arteries of DOCA-salt hypertension model: the role of endogenous ouabain

Grant number: 19/08026-5
Support type:Regular Research Grants
Duration: October 01, 2019 - September 30, 2021
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Luciana Venturini Rossoni
Grantee:Luciana Venturini Rossoni
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Hypertension, the multifactorial disease, characterized by high blood pressure (BP) levels, is the most common chronic disease in the Brazilian people. Among the mechanisms involved in the pathogenesis of this disease, the increment in plasma levels of Na+/ K+ ATPase inhibitors, such as ouabain (OUA), is observed. Higher sodium concentration associated with volume expansion, increase OUA synthesis and releases, which in turn modulates BP, by central and peripheral mechanisms. OUA activates sympathetic nervous system, through the renin-angiotensin-aldosterone system, as well as modulates norepinephrine release/ reuptake by the nerve endings in the perivascular tissue. Moreover, the increment in calcium handling, in vascular smooth muscle, the impairment of endothelial function; besides structural and mechanical remodeling in resistance arteries induced by OUA increase vascular tone. Together, these adjustments elevate peripheral vascular resistance and, consequently, BP.The mesenteric vascular bed is an important target of peripheral vascular resistance control, since it receives from 20 to 30% of the cardiac output, and, consequently, regulates the distribution of blood flow to the other parts of the body. Among the factors that control vascular tone in the mesenteric vascular bed, the nervous system stands out. Variations in the activity of the efferent pathways of perivascular innervation to the mesenteric bed, significantly alter the vascular diameter, modifying the resistance and the blood flow. Despite the importance of such bed, and knowledge of the effects of OUA on vascular function, there are few studies evaluating the influence of OUA on perivascular innervation and its components. In addition, resistance arteries of DOCA-salt rats present an inward hypertrophic remodeling accompanied by vascular stiffens, which are associated with higher angiotensin II- and/or endothelin-1-levels and hemodynamic forces (wall tension). Since OUA is related to release angiotensin II and endothelin-1, and its plasma levels are higher in the DOCA-salt HA model, OUA becomes a possible target for vascular remodeling in this volume-dependent hypertension model.Our research group was the first one to demonstrate that rostafuroxin (ROSTA) treatment, an antagonist of OUA signalossone action, in DOCA-salt rats reduces BP and improves endothelium-dependent relaxation (enhancing NO bioavailability and reducing ROS production). These effects were associated with reduced cSrc phosphorylation and no changes in Na+/ K+ ATPase activity. Thus, the major challenge of the present project is to understand the role of the endogenous OUA in the target organs lesions induced by HA, seeking to elucidate the functional and molecular mechanisms involved in the adjustments of perivascular innervation and remodeling in resistance arteries of the mesenteric bed. The aim of the present project is to evaluate the influence of endogenous OUA, through the use of ROSTA, on the activity of perivascular innervation components (adrenergic, nitrergic and sensory pathways) and structural and mechanical adjustments in resistance arteries of the mesenteric bed of the DOCA-salt model. (AU)