title: Cytochrome P-450 3A13 and endothelin jointly mediate ductus arteriosus constriction to oxygen in mice.
abstract: The fetal ductus arteriosus (DA) contracts to oxygen, and this feature, maturing through gestation, is considered important for its closure at birth. We have previously obtained evidence of the involvement of cytochrome P-450, possibly of the 3A subfamily (CYP3A), in oxygen sensing and have also identified endothelin (ET)-1 as the attendant effector for the contraction. Here, we examined comparatively wild-type (WT) and CYP3A-null (Cyp3a(-/-)) mice for direct validation of this concept. We found that the CYP3A subfamily is represented only by CYP3A13 in the WT DA. CYP3A13 was also detected in the DA by immunofluorescence microscopy, being primarily colocalized with the endoplasmic reticulum in both endothelial and muscle cells. However, a distinct signal was also evident in the plasma membrane. Isolated DAs from term WT animals developed a sustained contraction to oxygen with transient contractions superimposed. Conversely, no tonic response occurred in Cyp3a(-/-) DAs, whereas the phasic response persisted unabated. Oxygen did not contract the preterm WT DA but caused a full-fledged contraction after retinoic acid (RA) treatment. RA also promoted an oxygen contraction in the Cyp3a(-/-) DA. However, responses of RA-treated WT and Cyp3a(-/-) mice differed in that only the former abated with ET-1 suppression. This implies the existence of an alternative target for RA responsible for the oxygen-induced contraction in the absence of CYP3A13. In vivo, the DA was constricted in WT and Cyp3a(-/-) newborns, although with a tendency to be less narrowed in the mutant. We conclude that oxygen acts primarily through the complex CYP3A13 (sensor)/ET-1 (effector) and, in an accessory way, directly onto ET-1. However, even in the absence of CYP3A13, the DA may close postnatally thanks to the contribution of ET-1 and the likely involvement of compensating mechanism(s) identifiable with an alternative oxygen-sensing system and/or the withdrawal of relaxing influence(s) operating prenatally.
authors.affiliation: Scuola Superiore Sant'Anna, Piazza Martiri della Libertà 33, Pisa 56127, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Baragatti
authors.forename: Enrica
authors.initials: E
authors.lastname: Ciofini
authors.forename: Francesca
authors.initials: F
authors.lastname: Scebba
authors.forename: Debora
authors.initials: D
authors.lastname: Angeloni
authors.forename: Daria
authors.initials: D
authors.lastname: Sodini
authors.forename: Stefano
authors.initials: S
authors.lastname: Luin
authors.forename: Gian Michele
authors.initials: GM
authors.lastname: Ratto
authors.forename: Virginia
authors.initials: V
authors.lastname: Ottaviano
authors.forename: Eleonora
authors.initials: E
authors.lastname: Pagni
authors.forename: Aldo
authors.initials: A
authors.lastname: Paolicchi
authors.forename: Simona
authors.initials: S
authors.lastname: Nencioni
authors.forename: Flavio
authors.initials: F
authors.lastname: Coceani
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism / Q000502:physiology*; D004373:Ductus Arteriosus / Q000378:metabolism / Q000502:physiology*; D019332:Endothelin-1 / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000502:physiology; D010100:Oxygen / Q000378:metabolism / Q000502:physiology*; D014212:Tretinoin / Q000378:metabolism / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D019332:Endothelin-1; D008565:Membrane Proteins; D014212:Tretinoin; C496509:Cyp3a13 protein, mouse; D051544:Cytochrome P-450 CYP3A; D010100:Oxygen