PDF(Pubmed)
Abstract：
Intrauterine growth restriction (IUGR) is a common complication of pregnancy. We previously demonstrated that IUGR is associated with an impaired nitric oxide (NO)-induced relaxation in the human umbilical vein (HUV) of growth-restricted females compared to appropriate for gestational age (AGA) newborns. We found that phosphodiesterase (PDE) inhibition improved NO-induced relaxation in HUV, suggesting that PDEs could represent promising targets for therapeutic intervention. This study aimed to investigate the effects of PDE inhibition on human umbilical arteries (HUAs) compared to HUV. Umbilical vessels were collected in IUGR and AGA term newborns. NO-induced relaxation was studied using isolated vessel tension experiments in the presence or absence of the nonspecific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX). PDE1B, PDE1C, PDE3A, PDE4B, and PDE5A were investigated by Western blot. NO-induced vasodilation was similar between IUGR and AGA HUAs. In HUAs precontracted with serotonin, IBMX enhanced NO-induced relaxation only in IUGR females, whereas in HUV IBMX increased NO-induced relaxation in all groups except IUGR males. In umbilical vessels preconstricted with the thromboxane A2 analog U46619, IBMX improved NO-induced relaxation in all groups to a greater extent in HUV than HUAs. However, the PDE protein content was higher in HUAs than HUV in all study groups. Therefore, the effects of PDE inhibition depend on the presence of IUGR, fetal sex, vessel type, and vasoconstrictors implicated. Despite a higher PDE protein content, HUAs are less sensitive to IBMX than HUV, which could lead to adverse effects of PDE inhibition in vivo by impairment of the fetoplacental hemodynamics.NEW & NOTEWORTHY The effects of phosphodiesterase inhibition on the umbilical circulation depend on the presence of intrauterine growth restriction, the fetal sex, vessel type, and vasoconstrictors implicated. The human umbilical vascular tone regulation is complex and depends on the amount and activity of specific proteins but also probably on the subcellular organization mediating protein interactions. Therefore, therapeutic interventions using phosphodiesterase inhibitors to improve the placental-fetal circulation should consider fetal sex and both umbilical vein and artery reactivity.
摘要：
宫内生长受限（IUGR）是妊娠的常见并发症。我们先前证明，与适合胎龄（AGA）的新生儿相比，IUGR与生长受限的女性的人脐静脉（HUV）中一氧化氮（NO）诱导的松弛受损有关。我们发现磷酸二酯酶（PDE）抑制改善了HUV中NO诱导的弛豫，这表明PDE可能是治疗干预的有希望的目标。本研究旨在研究与HUV相比，PDE抑制对人脐动脉（HUAs）的影响。收集IUGR和AGA足月新生儿的脐血管。NO诱导的松弛使用孤立的血管张力实验进行了研究，在存在或不存在非特异性PDE抑制剂3-异丁基-1-甲基黄嘌呤（IBMX）的情况下。PDE1B,PDE1C,PDE3A,通过蛋白质印迹研究PDE4B和PDE5A。NO诱导的血管舒张在IUGR和AGAHUAs之间相似。在与血清素预签约的HUAs中，IBMX仅在IUGR雌性中增强NO诱导的松弛，而在HUV中，IBMX在除IUGR男性外的所有组中都增加了NO诱导的松弛。在血栓烷A2类似物U46619预收缩的脐血管中，IBMX改善了所有组的NO诱导舒张，在HUV比HUAs更大的程度。然而,HUAs中PDEs蛋白含量高于HUV，在所有学习小组中。因此,PDE抑制作用取决于IUGR的存在，胎儿性别,血管类型和血管收缩。尽管PDEs蛋白含量较高,HUA对IBMX的敏感性低于HUV，这可能导致体内PDE抑制的副作用，胎儿胎盘血流动力学受损。
