Reactive oxygen species as mediators of oxygen signaling during fetal-to-neonatal circulatory transition

Abstract

Reactive oxygen species (ROS) are frequently seen as pathological agents of oxidative stress. However, ROS are not always deleterious and can also act as cell signaling molecules. Vascular oxygen sensing and signaling during fetal-to-neonatal circulatory transition is a remarkable example of the physiological regulatory actions of ROS. The fetal relative hypoxic environment induces hypoxic pulmonary vasoconstriction (HPV) and ductus arteriosus (DA) relaxation favoring the presence of high pulmonary vascular resistance and right-to-left ductal shunt. At birth, the increase in oxygen tension causes relaxation of pulmonary arteries (PAs) and normoxic DA vasoconstriction (NDAV), thus diverting blood flow to the lungs. Although the response to changes in oxygen tension is diametrically opposite, the mechanisms responsible for HPV and NDAV appear to be the result of a similar interaction between triggering and modulating factors that lead to an increase in cytosolic Ca²⁺ concentration and Ca²⁺ sensitization of the contractile apparatus. Growing evidence points to an increase in ROS (mitochondria- and/or NADPH-derived superoxide and/or H₂O₂), leading to inhibition of voltage-gated K⁺ channels, membrane depolarization, and activation of voltage-gated L-type Ca²⁺ channels as critical events in the signaling pathway of both HPV and NDAV. Several groups of investigators have completed this pathway adding other elements such as neutral sphingomyelinase-derived ceramide, the sarcoplasmic/endoplasmic reticulum (through ryanodine and inositol 1,4,5-trisphosphate receptors), Rho kinase-mediated Ca²⁺ sensitization, or transient receptor potential channels. The present review focus on the role of ROS as mediators of the homeostatic oxygen sensing system during fetal and neonatal life not only in the PAs and DA but also in systemic arteries.

Keywords: Ceramide; Ductus arteriosus; Fetus; Hypoxic pulmonary vasoconstriction; Newborn; Pulmonary artery; Reactive oxygen species; Vascular oxygen signaling.