RESUMEN
BACKGROUND: Reactive oxygen species (ROS), including those produced by NADPH oxidase (NOX), play an important vasomotor role, especially at early postnatal period. Mechanisms for regulating vascular tone can change significantly due to neonatal asphyxia and accompanying hypoxia. We tested the hypothesis that normobaric hypoxia (8% O2) for 2 h at the second day of life changes the functional contribution of NOX-derived ROS to the regulation of agonist-induced contraction in early postnatal rats. METHODS: We studied saphenous arteries from 11- to 14-day-old male offspring using isometric myography and Western blotting and assessed the content of biochemical parameters in blood serum. RESULTS: The values of main biochemical parameters in blood serum and the protein content of NOXs and superoxide dismutases in arterial tissue did not differ between "Control" and "Hypoxia" pups. The NOX inhibitor VAS2870 equally reduced the contractile responses of arteries to α1-adrenoceptor agonist methoxamine in "Control" and "Hypoxia" pups, but its effect was more pronounced in the arteries from "Hypoxia" pups when vasocontraction was evoked by the agonist of thromboxane A2 receptors U46619. CONCLUSION: Perinatal hypoxia at the second day of life increases procontractile influence of NOX-derived ROS to the regulation of U46619-induced vasocontraction in the systemic arteries at early postnatal ontogenesis. IMPACT: Nothing is known about programming effects of perinatal hypoxia, including birth asphyxia, on the ROS-mediated regulation of contraction in systemic arteries of early postnatal organism. 2-h normobaric hypoxia (8% O2) in rats at the second day of life increases the procontractile contribution of NOX-produced ROS to the regulation of U46619-induced vasocontraction in the systemic arteries at early postnatal ontogenesis. This fact may serve as a risk factor for the development of various disorders at later developmental stages and should be considered regarding the therapy for newborns who have suffered neonatal asphyxia.
RESUMEN
Reactive oxygen species (ROS) produced by NADPH oxidases (NOX, a key source of ROS in vascular cells) are involved in the regulation of vascular tone, but this has been explored mainly for adult organisms. Importantly, the mechanisms of vascular tone regulation differ significantly in early postnatal ontogenesis and adulthood, while the vasomotor role of ROS in immature systemic arteries is poorly understood. We tested the hypothesis that the functional contribution of NADPH oxidase-derived ROS to the regulation of peripheral arterial tone is higher in the early postnatal period than in adulthood. We studied saphenous arteries from 10- to 15-day-old ("young") and 3- to 4-month-old ("adult") male rats using lucigenin-enhanced chemiluminescence, quantitative PCR, Western blotting, and isometric myography. We demonstrated that both basal and NADPH-stimulated superoxide anion radical (O2â¢-) production was significantly higher in the arteries from young in comparison to adult rats. Importantly, pan-inhibitor of NADPH oxidase VAS2870 (10 µM) reduced NADPH-induced O2â¢- production in arteries of young rats. Saphenous arteries of both young and adult rats demonstrated high levels of Nox2 and Nox4 mRNAs, while Nox1 and Nox3 mRNAs were not detected. The protein contents of NOX2 and NOX4 were significantly higher in arterial tissue of young compared to adult animals. Moreover, VAS2870 (10 µM) had no effect on methoxamine-induced contractile responses of adult arteries but decreased them significantly in young arteries; such effect of VAS2870 persisted after removal of the endothelium. Finally, NOX2 inhibitor GSK2795039 (10 µM), but not NOX1/4 inhibitor GKT137831 (10 µM) weakened methoxamine-induced contractile responses of arteries from young rats. Thus, ROS produced by NOX2 have a pronounced contractile influence in saphenous artery smooth muscle cells of young, but not adult rats, which is associated with the increased vascular content of NOX2 protein at this age.