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1 Institute of Neuroscience, CNR, Pisa, Italy
2 Settore di Scienze Mediche, Scuola Superiore Sant'Anna, Pisa, Italy; Institute of Clinical Physiology, CNR, Pisa, Italy
3 Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
4 Dulbecco Telethon Institute and Department of Endocrinology, University of Pisa, Pisa, Italy
5 Settore di Scienze Mediche, Scuola Superiore Sant'Anna, Pisa, Italy
* To whom correspondence should be addressed. E-mail: coceani{at}sssup.it.
Ductus arteriosus (DA) closure is initiated by oxygen rise postnatally and progresses in two, functional-to-permanent, stages. Here, using GeneChip Arrays in rat (normoxic and hyperoxic fetus, normoxic newborn), we examined whether oxygen alone duplicates the birth process in affecting DA genes. In addition, by comparing DA with aorta (Ao), we wished to identify features in postnatal gene profile marking transitional adjustments in a closing (DA) vs a persistent (Ao) vessel. We found changes in neonatal DA denoting enhanced formation and action of constrictor endothelin-1 (ET-1). Likewise, angiotensin II (Ang II) type 1 receptor was upregulated and the compound was a constrictor. Conversely, relaxant PGE2 became less effective. Among agents for functional closure, only ET-1 was similarly affected by oxygen and birth. Coincidentally, neonatal DA showed enhanced contractile drive with upregulation of Rho-Rho kinase and calcium signalling alongside with downregulation of contractile proteins. The latter effect was shared by oxygen. Changes denoting active remodeling were also seen in neonatal but not hyperoxic fetal DA. Ao, unlike DA, exhibited postnatal variations in noradrenergic, purinergic, and PGI2 systems with opposing effects on vasomotion. Contraction and remodeling processes were also less affected by birth, while lipid and glucose metabolism were upregulated. We conclude that several agents, including Ang II as novel effector, promote functional closure of DA, but only ET-1 is causally coupled with oxygen. Oxygen has no role in processes for permanent closure. Functional closure is associated with downregulation of contractile apparatus, and this may render neonatal DA less amenable to tone manipulation. Conceivably, activation of metabolism in neonatal Ao is a distinguishing feature for transitional adaptations in the permanent vasculature.
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