Maturation of O2 sensing and signaling in the chicken ductus arteriosus

Cogolludo AL, Moral-Sanz J, van der Sterren S, Frazziano G, van Cleef AN, Menendez C, Zoer B, Moreno E, Roman A, Perez-Vizcaino F, Villamor E. Maturation of O-2 sensing and signaling in the chicken ductus arteriosus. Am J Physiol Lung Cell Mol Physiol 297: L619-L630, 2009. First published July 17, 2009; doi:10.1152/ajplung.00092.2009.-The increase in O-2 tension after birth is a major factor stimulating ductus arteriosus (DA) constriction and closure. Here we studied the role of the mitochondrial electron transport chain (ETC) as sensor, H2O2 as mediator, and voltage-gated potassium (K-V) channels and Rho kinase as effectors of O-2-induced contraction in the chicken DA during fetal development. Switching from 0% to 21% O-2 contracted the pulmonary side of the mature DA ( mature pDA) but had no effect in immature pDA and relaxed the aortic side of the mature DA ( mature aDA). This contraction of the pDA was attenuated by inhibitors of the mitochondrial ETC and by the H2O2 scavenger polyethylene glycol (PEG)-catalase. Moreover, O-2 increased reactive oxygen species (ROS) production, measured with the fluorescent probes dihydroethidium and 2',7'-dichlorofluorescein, only in mature pDA. The H2O2 analog t-butyl-hydroperoxide mimicked the responses to O-2 in the three vessels. In contrast to immature pDA cells, mature pDA cells exhibited high-amplitude O-2-sensitive potassium currents. The KV channel blocker 4-aminopyridine prevented the current inhibition elicited by O-2. The L-type Ca2+ (Ca-L) channel blocker nifedipine and the Rho kinase inhibitors Y-27632 and hydroxyfasudil induced a similar relaxation when mature pDA were stimulated with O-2 or H2O2. Moreover, the sensitivity to these drugs increased with maturation. Our results indicate the presence of a common mechanism for O2 sensing/signaling in mammalian and nonmammalian DA and favor the idea that, rather than a single mechanism, a parallel maturation of the sensor and effectors is critical for O-2 sensitivity appearance during development.