Patterns of Gene Expression in the Ductus Arteriosus Are Related to Environmental and Genetic Risk Factors for Persistent Ductus Patency

Three independent risk factors (immature gestation, absence of antenatal glucocorticoid exposure, and presence of the rs2817399(A) allele of the gene TFAP2B) are associated with patent ductus arteriosus (PDAs) that fail to close during prostaglandin inhibition. We hypothesized that these three factors may affect a common set of genes that increase the risk of persistent PDA after birth. We studied baboon ductus from term, preterm, and glucocorticoid-treated preterm fetuses and found that both immature gestation and absence of antenatal glucocorticoid exposure decreased RNA expression of calcium- and potassium-channel genes involved in oxygen-induced constriction, and phosphodiesterase genes (that modulate cAMP/cGMP signaling). Ductus obtained from second trimester human pregnancies were genotyped for TFAP2B polymorphisms. When present, the rs2817399(A) allele also was associated with decreased expression of calcium- and potassium-channel genes. In contrast, alleles of two other TFAP2B polymorphisms, rs2817419(G) and rs2635727(T), which are not related to the incidence of PDA after birth, had no effect on RNA expression. In conclusion, three calcium- and potassium-channel genes (CACNA1G/ alpha1G, CACNB 2/CaL-beta2, and KCNA2/ Kv1.2) were similarly affected by each of the PDA risk factors. We speculate that these channels may play a significant role in closing the preterm ductus during prostaglandin inhibition and may be potential targets for future pharmacologic manipulations.

[1]  S. Poole,et al.  Chronic In Utero Cyclooxygenase Inhibition Alters PGE2-Regulated Ductus Arteriosus Contractile Pathways and Prevents Postnatal Closure , 2009, Pediatric Research.

[2]  Y. Ishikawa,et al.  T-type Ca2+ Channels Promote Oxygenation-induced Closure of the Rat Ductus Arteriosus Not Only by Vasoconstriction but Also by Neointima Formation* , 2009, The Journal of Biological Chemistry.

[3]  K. Johnson,et al.  Determination of Genetic Predisposition to Patent Ductus Arteriosus in Preterm Infants , 2009, Pediatrics.

[4]  S. Seidner,et al.  Oxygen-Induced Tension in the Sheep Ductus Arteriosus: Effects of Gestation on Potassium and Calcium Channel Regulation , 2009, Pediatric Research.

[5]  D. Mccurnin,et al.  Effects of a Patent Ductus Arteriosus on Postprandial Mesenteric Perfusion in Premature Baboons , 2008, Pediatrics.

[6]  V. Manganiello,et al.  Expression, Activity, and Function of Phosphodiesterases in the Mature and Immature Ductus Arteriosus , 2008, Pediatric Research.

[7]  D. Srivastava,et al.  Transcriptional Regulation During Development of the Ductus Arteriosus , 2008, Circulation research.

[8]  S. Archer,et al.  Developmental Absence of the O2 Sensitivity of L-Type Calcium Channels in Preterm Ductus Arteriosus Smooth Muscle Cells Impairs O2 Constriction Contributing to Patent Ductus Arteriosus , 2008, Pediatric Research.

[9]  L. Shulman.  Evaluation of Fetal and Maternal Genetic Variation in the Progesterone Receptor Gene for Contributions to Preterm Birth , 2008 .

[10]  P. Jegatheesan,et al.  Risk factors for persistent ductus arteriosus patency during indomethacin treatment. , 2007, The Journal of pediatrics.

[11]  C. Roman,et al.  Calcium-dependent and calcium-sensitizing pathways in the mature and immature ductus arteriosus. , 2007, American journal of physiology. Regulatory, integrative and comparative physiology.

[12]  S. Archer,et al.  Oxygen Activates the Rho/Rho-Kinase Pathway and Induces RhoB and ROCK-1 Expression in Human and Rabbit Ductus Arteriosus by Increasing Mitochondria-Derived Reactive Oxygen Species: A Newly Recognized Mechanism for Sustaining Ductal Constriction , 2007, Circulation.

[13]  R. Clyman,et al.  Patent ductus arteriosus: evidence for and against treatment. , 2007, The Journal of pediatrics.

[14]  A. Varghese,et al.  Role of Store-Operated Calcium Channels and Calcium Sensitization in Normoxic Contraction of the Ductus Arteriosus , 2006, Circulation.

[15]  B. Vásárhelyi,et al.  Association of interferon γ T+874A and interleukin 12 p40 promoter CTCTAA/GC polymorphism with the need for respiratory support and perinatal complications in low birthweight neonates , 2006, Archives of Disease in Childhood - Fetal and Neonatal Edition.

[16]  N. Socci,et al.  Gene expression in ductus arteriosus and aorta: comparison of birth and oxygen effects. , 2006, Physiological genomics.

[17]  B. Yoder,et al.  Effect of ductus ligation on cardiopulmonary function in premature baboons. , 2005, American journal of respiratory and critical care medicine.

[18]  R. Keller,et al.  Combined Treatment With a Nonselective Nitric Oxide Synthase Inhibitor (L-NMMA) and Indomethacin Increases Ductus Constriction in Extremely Premature Newborns , 2005, Pediatric Research.

[19]  M. State,et al.  Syndromic patent ductus arteriosus: evidence for haploinsufficient TFAP2B mutations and identification of a linked sleep disorder. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[20]  K. Momma,et al.  Increased constriction of the ductus arteriosus by dexamethasone, indomethacin, and rofecoxib in fetal rats. , 2005, Circulation journal : official journal of the Japanese Circulation Society.

[21]  B. Vásárhelyi,et al.  Gender dependent association between perinatal morbidity and estrogen receptor-alpha Pvull polymorphism , 2005, Journal of perinatal medicine.

[22]  T. Scholz,et al.  Early gestation dexamethasone programs enhanced postnatal ovine coronary artery vascular reactivity. , 2005, American journal of physiology. Regulatory, integrative and comparative physiology.

[23]  D. Ginzinger,et al.  Prostaglandin E2—Mediated Relaxation of the Ductus Arteriosus: Effects of Gestational Age on G Protein-Coupled Receptor Expression, Signaling, and Vasomotor Control , 2004, Circulation.

[24]  J. Dyck,et al.  Oxygen-Sensitive Kv Channel Gene Transfer Confers Oxygen Responsiveness to Preterm Rabbit and Remodeled Human Ductus Arteriosus: Implications for Infants With Patent Ductus Arteriosus , 2004, Circulation.

[25]  B. Vásárhelyi,et al.  Angiotensin II Type 1 Receptor A1166C Polymorphism and Prophylactic Indomethacin Treatment Induced Ductus Arteriosus Closure in Very Low Birth Weight Neonates , 2003, Pediatric Research.

[26]  B. Gelb,et al.  Novel TFAP2B mutations that cause Char syndrome provide a genotype-phenotype correlation. , 2001, American journal of human genetics.

[27]  B. Schmidt,et al.  Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. , 2001, The New England journal of medicine.

[28]  G. Andelfinger,et al.  Characterization of PGE2 receptors in fetal and newborn lamb ductus arteriosus. , 2001, American journal of physiology. Heart and circulatory physiology.

[29]  R. Buettner,et al.  Regulatory roles of AP-2 transcription factors in vertebrate development, apoptosis and cell-cycle control. , 2000, Gene.

[30]  B. Yoder,et al.  High-frequency oscillatory ventilation: effects on lung function, mechanics, and airway cytokines in the immature baboon model for neonatal chronic lung disease. , 2000, American journal of respiratory and critical care medicine.

[31]  S. Wellek,et al.  Age-Related Reference Ranges for Fetal Foot Length , 2000, Ultraschall in der Medizin.

[32]  C. Ackerley,et al.  Endothelin A receptor is necessary for O2 constriction but not closure of ductus arteriosus. , 1999, American journal of physiology. Heart and circulatory physiology.

[33]  B. Yoder,et al.  Neonatal chronic lung disease in extremely immature baboons. , 1999, American journal of respiratory and critical care medicine.

[34]  A. Brem,et al.  Glucocorticoids inhibit the expression of calcium-dependent potassium channels in vascular smooth muscle. , 1999, Molecular genetics and metabolism.

[35]  C. Ackerley,et al.  Endothelin A receptor is necessary for O(2) constriction but not closure of ductus arteriosus. , 1999, The American journal of physiology.

[36]  I. Miyamori,et al.  Dexamethasone modulates the expression of endothelin-1 and -A receptors in A7r5 vascular smooth muscle cells. , 1998, Journal of cardiovascular pharmacology.

[37]  S. Black,et al.  Regulation of Ductus Arteriosus Patency by Nitric Oxide in Fetal Lambs: The Role of Gestation, Oxygen Tension, and Vasa Vasorum , 1998, Pediatric Research.

[38]  K. Zerres,et al.  Enhanced apoptotic cell death of renal epithelial cells in mice lacking transcription factor AP-2beta. , 1997, Genes & development.

[39]  J. Rüschoff,et al.  Comparative analysis of AP‐2α and AP‐2β gene expression during murine embryogenesis , 1997 .

[40]  J. Rüschoff,et al.  Comparative analysis of AP-2 alpha and AP-2 beta gene expression during murine embryogenesis. , 1997, Developmental dynamics : an official publication of the American Association of Anatomists.

[41]  J. Hynes,et al.  Study on the mechanisms of glucocorticoid-induced hypertension: glucocorticoids increase transmembrane Ca2+ influx in vascular smooth muscle in vivo. , 1995, Endocrine research.

[42]  J. Smith,et al.  Regulation of sodium-calcium exchanger by glucocorticoids and growth factors in vascular smooth muscle. , 1994, The Journal of biological chemistry.

[43]  S. Miyabo,et al.  Glucocorticoids increase Ca2+ uptake and [3H]dihydropyridine binding in A7r5 vascular smooth muscle cells. , 1991, The American journal of physiology.