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Possible linkage of beta-adrenergic overstimulation to mineralocorticoid receptor activation in endothelial, smooth muscle and adipocyte vascular cells

Grant number: 14/07947-6
Support Opportunities:Regular Research Grants
Duration: February 01, 2015 - July 31, 2017
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Ana Paula Couto Davel
Grantee:Ana Paula Couto Davel
Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated researchers:Maria Andréia Delbin


Sustained stimulation of beta-adrenoceptors (beta-AR) is associated high mortality in cardiovascular diseases as heart failure and arterial hypertension. Despite many studies on the role of beta-AR overstimulation on cardiac function, little is known about its effects on vascular function. Chronic beta-AR activation can be achieved by daily administration of isoproterenol (ISO), a non-selective beta-AR agonist. We previously demonstrated that in vivo ISO treatment induced endothelial dysfunction, oxidative stress and increased contractile response to agonists in murine aorta. These effects were associated with enhanced activity and expression of Gai protein and MAPKs (mitogen-activated protein kinase), and uncoupling of endothelial nitric oxide synthase (eNOS), which reduces synthesis and bioavailability of the endothelial NO. Interestingly, the mineralocorticoid receptor (MR) antagonist spironolactone reversed these adverse vascular effects of chronic beta-AR activation, without significant hemodynamic effects or changes in plasma levels of aldosterone and corticosterone. It suggested a possible linkage between beta-AR and MR vascular signaling, in a way that beta-AR overstimulation induce MR signaling pathway, independently of systemic effects. However, the following questions remain unclear: 1) could the chronic beta-AR stimulation induce local synthesis of aldosterone and/or glucocorticoids, or even modulate their action in vascular (endothelial and smooth muscle) and perivascular adipocyte cells (PVAT)? 3) could the beta-AR stimulation directly activate MR signaling? 3) which is the cellular pathway involved in eNOS uncoupling and oxidative stress induced by beta-AR stimulation dependent on MR activation? Considering that endothelial, smooth muscle and adipose cells express functional beta-AR e MR and the enzymes to synthesize aldosterone and glucocorticoids, we hypothesized a role for vascular and perivascular MR-activated signaling pathway on the effects of beta-AR overstimulation inducing eNOS uncoupling, endothelial dysfunction, oxidative stress and impaired vascular reactivity. To reach the aim od the project, Wistar rats and endothelial, smooth muscle and adipocyte cells will be exposed to isoproterenol (beta-AR agonist) in vivo and in vitro, respectively, and co-treated with a MR antagonist. In isolated aorta and PVAT from treated rats, as well as in the cultured cells, it will be evaluated: aldosterone and corticosterone production; signaling pathway involved in the synthesis of aldosterone and corticosterone and vascular MR activation; beta-AR signaling coupled to Gs and Gi proteins; NO and reactive oxygen species production. (AU)

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Scientific publications
(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)
VICTORIO, JAMAIRA A.; CLERICI, STEFANO P.; PALACIOS, ROBERTO; ALONSO, MARIA J.; VASSALLO, DALTON V.; JAFFE, IRIS Z.; ROSSONI, LUCIANA V.; DAVEL, ANA P.. Spironolactone Prevents Endothelial Nitric Oxide Synthase Uncoupling and Vascular Dysfunction Induced by beta-Adrenergic Overstimulation Role of Perivascular Adipose Tissue. Hypertension, v. 68, n. 3, p. 726+, . (11/15972-2, 14/07947-6)
FRANCO, NATHALIA DA SILVA; LUBACZEUSKI, CAMILA; GUIZONI, DANIELE M.; VICTORIO, JAMAIRA A.; SANTOS-SILVA, JUNIA C.; BRUM, PATRICIA C.; CARNEIRO, EVERARDO M.; DAVEL, ANA P.. Propranolol treatment lowers blood pressure, reduces vascular inflammatory markers and improves endothelial function in obese mice. PHARMACOLOGICAL RESEARCH, v. 122, p. 35-45, . (15/00074-0, 14/07947-6)
VICTORIO, JAMAIRA A.; FONTES, MILENE T.; ROSSONI, LUCIANA V.; DAVEL, ANA P.. Different Anti-Contractile Function and Nitric Oxide Production of Thoracic and Abdominal Perivascular Adipose Tissues. FRONTIERS IN PHYSIOLOGY, v. 7, . (14/20303-0, 14/07947-6)

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