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Am J Physiol Lung Cell Mol Physiol 297: L619-L630, 2009. First published July 17, 2009; doi:10.1152/ajplung.00092.2009
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Maturation of O2 sensing and signaling in the chicken ductus arteriosus

Angel L. Cogolludo,1,2 Javier Moral-Sanz,1 Saskia van der Sterren,2 Giovanna Frazziano,1 Anne N. H. van Cleef,2 Carmen Menéndez,1 Bea Zoer,2 Enrique Moreno,1 Angela Roman,1 Francisco Pérez-Vizcaino,1 and Eduardo Villamor2

1Department of Pharmacology, School of Medicine, Universidad Complutense Madrid and Centro de Investigaciones Biomedicas en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain; and ; 2Department of Pediatrics, Maastricht University Medical Center, School for Oncology and Developmental Biology, Maastricht, The Netherlands

Submitted 18 March 2009 ; accepted in final form 9 July 2009

The increase in O2 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 (KV) channels and Rho kinase as effectors of O2-induced contraction in the chicken DA during fetal development. Switching from 0% to 21% O2 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, O2 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 O2 in the three vessels. In contrast to immature pDA cells, mature pDA cells exhibited high-amplitude O2-sensitive potassium currents. The KV channel blocker 4-aminopyridine prevented the current inhibition elicited by O2. The L-type Ca2+ (CaL) channel blocker nifedipine and the Rho kinase inhibitors Y-27632 and hydroxyfasudil induced a similar relaxation when mature pDA were stimulated with O2 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 O2 sensitivity appearance during development.

oxygen sensing; potassium channels; hydrogen peroxide


Address for reprint requests and other correspondence: A. L. Cogolludo, Dept. of Pharmacology, School of Medicine, Universidad Complutense Madrid, Ciudad Universitaria S/N, 28040 Madrid, Spain (e-mail: acogolludo{at}med.ucm.es).






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