Influência da via das quinureninas na função vascular de camundongos prenhe e não prenhe em modelo de animais hiperglicêmicos

Abstract

Diabetes Mellitus (DM) is among the most prevalent chronic non-communicable diseases (NCDs) in Brazil and around the world, not only because of the damage to the population's health, but also because of its high mortality rate. When it happens in the pregnant state, it can compromise the mother's life and fetal development, as well as predispose the mother to the development of DM2. Macro and microvascular alterations present in this pathology, in addition to activation of inflammatory pathways that culminate in vascular dysfunction, have been related to altered levels of metabolites from the kynurenine pathway. This pathway results from tryptophan metabolism by enzymes such as indoleamine 2,3-dioxygenase (IDO), whose expression is increased in inflammatory conditions. Thus, the present study aimed to investigate the relationship of the kynurenine pathway with vascular adaptations associated with pregnancy and its relationship with vascular disorders induced by hyperglycemia in mouse arteries. To carry out the experimental protocols, female mice were used to compose four experimental groups: normoglycemic, hyperglycemic, normoglycemic pregnant and hyperglycemic pregnant (n=10/group). The animals in the hyperglycemic group were submitted to a hypercaloric diet for 3 months. During this period, they received two doses of streptozotocin (100mg/kg) with an interval of one week between applications. The animals in the hyperglycemic pregnant group were submitted to a hypercaloric diet during the month before mating and during the 21 days of pregnancy. Hyperglycemia was confirmed with the glycemic dosages of animals fasting for 6h. All groups went through essays of vascular reactivity, in which the vasoconstrictor response induced by phenylephrine and vasodilator induced by acetylcholine in aortic rings of mice, which were previously incubated with inhibitors of indoleamine2,3-dioxygenase (IDO) and kynurenine mono-oxygenase (KMO) or with metabolites from the pathway: L-kynurenine (KYN), kynurenic acid (Ac. KYN) and 3-hydroxykynurenine (3HKYN). Our results showed that the kynurenine pathway plays an important role in regulating vascular tone in the four experimental groups. This regulation was directed to a decrease in the vascular response to the vasoconstrictor phenylephrine. In addition, we also evidenced that the pathway activation profile differs in the evaluated groups. The action of kynurenic acid was more expressive in pregnancy and kynurenine in hyperglycemic pregnancy. While in the non-pregnant condition, we suggest that other metabolites, not evaluated in this study, may trigger this vasculature regulating action, since incubation with the inhibitors promoted vascular changes, and the same was not seen with the analyzed metabolites.