Chronic In Utero Cyclooxygenase Inhibition Alters PGE2-Regulated Ductus Arteriosus Contractile Pathways and Prevents Postnatal Closure
Chronic In Utero Cyclooxygenase Inhibition Alters PGE2-Regulated Ductus Arteriosus Contractile Pathways and Prevents Postnatal Closure
复制标题
DOI：
10.1203/pdr.0b013e3181aa07eb
复制
发表时间：
2009-08-01
影响因子：
3.6
通讯作者：
Clyman, Ronald I.
中科院分区：
文献类型：
--
作者：
Reese, Jeff;Waleh, Nahid;Clyman, Ronald I.
虽然前列腺素E2（PGE 2）可扩张动脉导管，但使用环氧合酶（考克斯）抑制剂安胎可延迟出生后动脉导管闭合。我们使用胎鼠和绵羊来确定PGE 2是否在导管收缩力的发展中起作用，这与其作为血管扩张剂的功能不同。在体外，胎儿导管长期暴露于PGE 2增加了CaL和K+通道基因（CaL α 1c、CaL β 2、Kir6.1和Kv1.5，它们调节氧诱导的收缩）的表达，而不影响调节Rho激酶介导的钙敏感性的基因。相反，子宫内长期暴露于考克斯抑制剂可降低CaL和K+通道基因的表达，而不影响Rho激酶相关基因。子宫内慢性考克斯抑制降低了导管对CaL-和K+-通道（如O-2和K+）刺激的体外收缩反应，而对Rho激酶介导途径（如U46619）刺激的反应没有显著影响。磷酸二酯酶表达降低了导管对cAMP或cGMP依赖性血管扩张剂的敏感性，分别通过PGE 2暴露增加和通过考克斯抑制剂降低。这些研究确定了PGE 2介导的发育程序的潜在下游效应物，调节氧诱导的导管闭合。这些效应物的改变可以解释子宫内考克斯抑制后动脉导管未闭（PDA）风险增加的原因。（儿科研究66：155- 161，2009）
Although prostaglandin E2 (PGE2) vasodilates the ductus arteriosus, tocolysis with cyclooxygenase (COX) inhibitors delays postnatal ductus arteriosus closure. We used fetal mice and sheep to determine whether PGE2 has a role in the development of ductus contractility that is distinct from its function as a vasodilator. Prolonged exposure of fetal ductus to PGE2 in vitro increased the expression of CaL- and K+-channel genes (CaL alpha 1c, CaL beta 2, Kir6.1, and Kv1.5, which regulate oxygen-induced constriction) without affecting the genes that regulate Rho-kinase-mediated calcium sensitization. Conversely, chronic exposure to COX inhibitors in utero decreased expression of CaL- and K+-channel genes, without affecting Rho-kinase-associated genes. Chronic COX inhibition in utero decreased the ductus' in vitro contractile response to stimuli that use CaL- and K+-channels (like O-2, and K+), whereas the response to stimuli that act through Rho-kinase-mediated pathways (like U46619) wits not significantly affected. Phosphodiesterase expression, which decreases the ductus' sensitivity to cAMP- or cGMP-dependent vasodilators, was increased by PGE2 exposure and decreased by COX inhibition, respectively. These Studies identify potential downstream effectors of a PGE2-mediated, developmental program, regulating oxygen-induced ductus closure. Alterations In these effectors may explain the increased risk of patent ductus arteriosus (PDA) after in utero COX inhibition. (Pediatr Res 66: 155-161,2009)