title: Postnatal constriction, ATP depletion, and cell death in the mature and immature ductus arteriosus.
abstract: After birth, constriction of the full-term ductus arteriosus induces oxygen, glucose and ATP depletion, cell death, and anatomic remodeling of the ductus wall. The immature ductus frequently fails to develop the same degree of constriction or anatomic remodeling after birth. In addition, the immature ductus loses its ability to respond to vasoconstrictive agents, like oxygen or indomethacin, with increasing postnatal age. We examined the effects of premature delivery and postnatal constriction on the immature baboon ductus arteriosus. By 6 days after birth, surrogate markers of hypoxia (HIF1alpha/VEGF mRNA) and cell death [dUTP nick-end labeling (TUNEL)-staining] increased, while glucose and ATP concentrations (bioluminescence imaging) decreased in the immature ductus. TUNEL-staining was significantly related to the degree of glucose and ATP depletion. Glucose and ATP depletion were directly related to the degree of ductus constriction; while TUNEL-staining was logarithmically related to the degree of ductus constriction. Extensive cell death (>15% TUNEL-positive cells) occurred only when there was no Doppler flow through the ductus lumen. In contrast, HIF1alpha/VEGF expression and ATP concentrations were significantly altered even when the immature ductus remained open after birth. Decreased ATP concentrations produced decreased oxygen-induced contractile responses in the immature ductus. We hypothesize that ATP depletion in the persistently patent immature newborn ductus is insufficient to induce cell death and remodeling but sufficient to decrease its ability to constrict after birth. This may explain its decreasing contractile response to oxygen, indomethacin, and other contractile agents with increasing postnatal age.
authors.affiliation: Wallenberg Laboratory for Cardiovascular Rsearch, Göteborg University, Göteborg, Sweden.
authors.forename: Max
authors.initials: M
authors.lastname: Levin
authors.forename: Don
authors.initials: D
authors.lastname: McCurnin
authors.forename: Steven R
authors.initials: SR
authors.lastname: Seidner
authors.forename: Bradley
authors.initials: B
authors.lastname: Yoder
authors.forename: Nahid
authors.initials: N
authors.lastname: Waleh
authors.forename: Seth
authors.initials: S
authors.lastname: Goldbarg
authors.forename: Christine
authors.initials: C
authors.lastname: Roman
authors.forename: Bao Mei
authors.initials: BM
authors.lastname: Liu
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.forename: Ronald I
authors.initials: RI
authors.lastname: Clyman
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death; D004373:Ductus Arteriosus / Q000378:metabolism* / Q000473:pathology* / Q000502:physiology / Q000503:physiopathology; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D010215:Papio; D012756:Sheep; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D000255:Adenosine Triphosphate; D006003:Glycogen; D005947:Glucose