Postnatal constriction, ATP depletion, and cell death in the mature and immature ductus arteriosus

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2006-02, Vol.290 (2), p.R359-R364
• Main Authors: Levin, Max, McCurnin, Don, Seidner, Steven R, Yoder, Bradley, Waleh, Nahid, Goldbarg, Seth, Roman, Christine, Liu, Bao Mei, Boren, Jan, Clyman, Ronald I
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; alpha Subunit/metabolism; Animals; Animals, Newborn; Anoxia; Cell Death; Ductus Arteriosus - metabolism; Ductus Arteriosus - pathology; Ductus Arteriosus - physiology; Ductus Arteriosus - physiopathology; Ductus Arteriosus/metabolism/pathology/physiology/physiopathology; Gene Expression Regulation; Glucose - metabolism; Glycogen - metabolism; Hypoxia; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; MEDICAL AND HEALTH SCIENCES; MEDICIN OCH HÄLSOVETENSKAP; Newborn; Papio; Sheep; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00629.2005

1 Cardiovascular Research Institute and Department of Pediatrics, University of California, San Francisco; 2 Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Göteborg, Sweden, Departments of 3 Pediatrics and 4 Pathology, University of Texas Health Science Center, San Antonio, Texas; 5 SRI International, Menlo Park, California Submitted 30 August 2005 ; accepted in final form 9 October 2005 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 (HIF1 /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, HIF1 /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. baboon; hypoxia; glucose; glycogen; HIF1 Address for reprint requests and other correspondence: R. I. Clyman, Box 0544, HSW 1408, Univ. of California, San Francisco, 513 Parnassus Ave., San Francisco, CA 94143–0544 (e-mail: clymanr{at}peds.ucsf.edu )