孕妇年龄高(≥35岁)会增加妊娠并发症的风险,例如先兆子痫和胎儿生长受限。我们先前在高龄大鼠模型中证明了血管功能障碍和异常妊娠结局。然而,没有研究衰老过程中血管对妊娠的适应.我们假设,由于一氧化氮(NO)减少和基质金属蛋白酶(MMPs)活性增加,高龄产妇年龄与血管收缩表型有关。导致妊娠血管适应性受损。使用高龄的大鼠模型:年轻(4个月)和年龄(9.5个月;人类〜35岁)的非怀孕和怀孕大鼠。在妊娠第20天(足月=22天;非妊娠大鼠年龄匹配),测量血压和心率(尾袖体积描记术),并评估肠系膜动脉的血管功能(钢丝肌电图)。在存在/不存在一氧化氮合酶抑制剂(L-NAME)的情况下,评估了对甲基胆碱(MCh)的内皮依赖性松弛,或内皮依赖性超极化抑制剂(EDH;apamin和TRAM-34)。对大内皮素-1(bigET-1)的血管收缩反应,在存在/不存在MMPs抑制剂(GM6001)或内皮素转化酶(ECE-1)抑制剂(CGS35066)的情况下,此外,ET-1响应能力,被测量。与所有其他组相比,仅老年非妊娠大鼠的血压升高(p<0.001)。MCh反应没有什么不同,然而,L-NAME降低了幼鼠(p<0.01)和老年孕鼠(p<0.001)的最大血管舒张功能,幼年非妊娠大鼠MCh敏感性降低(p<0.01),对老年非妊娠大鼠没有影响。EDH对放松的贡献在未怀孕的年轻人中相似,和老年非怀孕和怀孕的老鼠,而EDH介导的松弛在年轻怀孕大鼠中不存在(p<0.001)。BigET-1反应在老年非妊娠大鼠(p<0.01)和妊娠大鼠(p<0.05)中增强。在存在MMP抑制剂的情况下,bigET-1转化没有显著变化,而ECE-1抑制可降低老年大鼠bigET-1收缩(p<0.01)。未观察到ET-1敏感性的差异。总之,与我们的假设相反,血压降低,EDH依赖性血管舒张功能的增加提示了一种代偿机制,该机制可能反映了这些能够维持妊娠的老年大鼠的有益适应。这些数据增加了我们对怀孕中的血管适应性途径如何补偿孕妇高龄的理解。
Advanced maternal age (≥35 years old) increases the risk of pregnancy complications such as preeclampsia and fetal growth restriction. We previously demonstrated vascular dysfunction and abnormal pregnancy outcomes in a rat model of advanced maternal age. However, vascular adaptations to pregnancy in aging were not studied. We hypothesize that advanced maternal age is associated with a more vasoconstrictive phenotype due to reduced nitric oxide (NO) and increased activity of matrix metalloproteinases (MMPs), contributing to impaired vascular adaptations to pregnancy. A rat model of advanced maternal age was used: young (4 months) and aged (9.5 months; ∼35 years in humans) non-pregnant and pregnant rats. On gestational day 20 (term = 22 days; non-pregnant rats were aged-matched), blood pressure and heart rate were measured (tail cuff plethysmography) and vascular function was assessed in mesenteric arteries (wire myography). Endothelium-dependent relaxation to methylcholine (MCh) was assessed in the presence/absence of nitric oxide synthase inhibitor (L-NAME), or inhibitors of endothelium-dependent hyperpolarization (EDH; apamin and TRAM-34). Vasoconstriction responses to big endothelin-1 (bigET-1), in the presence/absence of MMPs-inhibitor (GM6001) or endothelin converting enzyme (ECE-1) inhibitor (CGS35066), in addition, ET-1 responsiveness, were measured. Blood pressure was elevated only in aged non-pregnant rats (p < 0.001) compared to all other groups. MCh responses were not different, however, L-NAME decreased maximum vasodilation in young (p < 0.01) and aged pregnant rats (p < 0.001), and decreased MCh sensitivity in young non-pregnant rats (p < 0.01), without effects in aged non-pregnant rats. EDH contribution to relaxation was similar in young non-pregnant, and aged non-pregnant and pregnant rats, while EDH-mediated relaxation was absent in young pregnant rats (p < 0.001). BigET-1 responses were enhanced in aged non-pregnant (p < 0.01) and pregnant rats (p < 0.05). No significant changes in bigET-1 conversion occurred in the presence of MMP-inhibitor, whereas ECE-1 inhibition reduced bigET-1 constriction in aged rats (p < 0.01). No differences in ET-1 sensitivity were observed. In conclusion, contrary to our hypothesis, reduced blood pressure, and an increased EDH-dependent contribution to vasodilation suggest a compensatory mechanism that may reflect beneficial adaptations in these aged rats that were able to maintain pregnancy. These data increase our understanding of how the vascular adaptive pathways in pregnancy compensate for advanced maternal age.