Osikoya Oluwatobiloba, Jaini Paresh A, Nguyen An, Valdes Melissa, Goulopoulou Styliani
Institute for Cardiovascular and Metabolic Disease, University of North Texas Health Science Center, Fort Worth, TX, USA.
Institute for Cardiovascular and Metabolic Disease, University of North Texas Health Science Center, Fort Worth, TX, USA.
Pharmacol Res. 2017 Jun;120:267-278. doi: 10.1016/j.phrs.2017.04.012. Epub 2017 Apr 12.
Daily intake of low-dose aspirin after 12weeks of gestation is currently recommended as a preventative intervention in pregnancies in high risk of developing preeclampsia. This recommendation is based on epidemiological evidence, whereas experimental studies investigating the exact mechanisms of aspirin action during pregnancy are lacking. We previously showed that treating pregnant rats with a synthetic mimetic of unmethylated CpG DNA (bacterial DNA) caused preeclampsia-like characteristics such as maternal hypertension and increased cyclooxygenase (COX) expression and activity. In this study, we tested the hypothesis that daily maternal treatment with low-dose aspirin would prevent the development of maternal hypertension, reduce COX activity and thromboxane A (TxA) production, and improve maternal vascular function in pregnant rats exposed to CpG ODN during gestation. Pregnant rats were treated with ODN2395 (synthetic CpG DNA) or saline (vehicle) on gestational days (GD) 14, 16, 18. Daily low-dose aspirin treatment (1.5mg/kgBW) started on GD10 and continued throughout gestation. Pregnant rats treated with ODN2395 had greater systolic blood pressure compared to controls (120±4mmHg vs. 100±5mmHg, p=0.03) and aspirin did not prevent this increase (p=0.86). Aspirin prevented ODN2395-induced increases of TxB (TxA metabolite) in serum and mesenteric arteries. ODN2395 increased expression of COX-1 and COX-2 in mesenteric and uterine arteries and aspirin abolished these effects. Aspirin reduced contractile responses to phenylephrine and U46619 (TxA mimetic) in mesenteric arteries from control rats but not from ODN2395-treated rats. In conclusion, treatment with low-dose aspirin reduced systemic and vascular COX expression and activity but did not prevent the development of maternal hypertension induced by exposure to unmethylated CpG DNA (bacterial DNA).
目前建议在妊娠12周后每日摄入低剂量阿司匹林，作为预防子痫前期高危妊娠的一种干预措施。这一建议基于流行病学证据，然而，缺乏关于阿司匹林在孕期作用的确切机制的实验研究。我们之前表明，用未甲基化CpG DNA（细菌DNA）的合成模拟物处理怀孕大鼠会导致子痫前期样特征，如母体高血压以及环氧化酶（COX）表达和活性增加。在本研究中，我们检验了以下假设：孕期母体每日接受低剂量阿司匹林治疗可预防母体高血压的发生，降低COX活性和血栓素A（TxA）生成，并改善孕期暴露于CpG ODN的怀孕大鼠的母体血管功能。在妊娠第14、16、18天，给怀孕大鼠注射ODN2395（合成CpG DNA）或生理盐水（载体）。从妊娠第10天开始每日进行低剂量阿司匹林治疗（1.5mg/kg体重），并持续整个孕期。与对照组相比，接受ODN2395治疗的怀孕大鼠收缩压更高（120±4mmHg对100±5mmHg，p = 0.03），而阿司匹林未能预防这种升高（p = 0.86）。阿司匹林可预防ODN2395诱导的血清和肠系膜动脉中TxB（TxA代谢产物）的增加。ODN2395增加了肠系膜动脉和子宫动脉中COX-1和COX-2的表达，而阿司匹林消除了这些作用。阿司匹林降低了对照组大鼠肠系膜动脉对去氧肾上腺素和U46619（TxA模拟物）的收缩反应，但对接受ODN2395治疗的大鼠无效。总之，低剂量阿司匹林治疗可降低全身和血管COX的表达及活性，但不能预防暴露于未甲基化CpG DNA（细菌DNA）所致的母体高血压的发生。
