Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
Faculty of Forestry, University of British Columbia, Vancouver, BC, Canada.
Clin Exp Hypertens. 2024 Dec 31;46(1):2402260. doi: 10.1080/10641963.2024.2402260. Epub 2024 Sep 20.
Gestational diabetes can lead to increased blood pressure in offspring, accompanied by impaired renal sodium excretion function and vasoconstriction and diastole dysfunction. However, there are few studies on whether it is accompanied by increased sympathetic nerve activity.
Pregnant C57BL/6 mice were intraperitoneally injected with streptozotocin (35 mg/kg) or citrate buffer at day 0 of gestation. The mice of control mother offspring (CMO) and diabetic mother offspring (DMO) at 16 weeks of age were infused with vehicle (artificial cerebrospinal fluid, aCSF, 0.4 μL/h) or tempol (1 mmol/L, 0.4 μL/h) into the bilateral paraventricular nucleus (PVN) of mice for 4 weeks, respectively.
Compared with CMO group, SBP and peripheral sympathetic nerve activity (increased heart rate, LF/HF and plasma norepinephrine and decreased SDNN and RMSSD) were increased in DMO group, which was accompanied by increased angiotensin II type-1 receptor (ATR) expression and function in PVN. The increase in ATR expression levels was attributed to a decrease in the methylation level of the ATR promoter region, resulting in an increase in ATR mRNA levels in PVN of DMO. Moreover, compared with CMO group, the levels of oxidative stress were increased and DNMT1 expression was decreased in PVN of DMO. Bilateral PVN infusion of tempol attenuated oxidative stress increased the level of DNMT1 expression and the binding of DNMT1 to the ATR promoter region, which reduced mRNA and protein expression level of ATR, heart rate and SBP in DMO, but not in CMO.
The present study provides evidence for overactive sympathetic nervous systems in the pathogenesis of gestational diabetes-induced hypertension in offspring. Central antioxidant intervention in the PVN may be an important treatment strategy for fetal-programmed hypertension.
妊娠糖尿病可导致后代血压升高，伴有肾钠排泄功能障碍、血管收缩和舒张功能障碍。然而，关于其是否伴有交感神经活性增加的研究较少。
妊娠 0 天的 C57BL/6 小鼠经腹腔注射链脲佐菌素（35mg/kg）或柠檬酸缓冲液。16 周龄时，对照组母鼠后代（CMO）和糖尿病母鼠后代（DMO）分别接受vehicle（人工脑脊液，aCSF，0.4μL/h）或tempol（1mmol/L，0.4μL/h）双侧室旁核（PVN）输注 4 周。
与 CMO 组相比，DMO 组 SBP 和外周交感神经活性（心率增加、LF/HF 和血浆去甲肾上腺素增加，SDNN 和 RMSSD 减少）增加，PVN 中血管紧张素 II 型 1 受体（ATR）表达和功能增加。ATR 表达水平的增加归因于 ATR 启动子区域的甲基化水平降低，导致 DMO 中 PVN 的 ATR mRNA 水平增加。此外，与 CMO 组相比，DMO 的 PVN 氧化应激水平增加，DNMT1 表达减少。双侧 PVN 输注 tempol 可减轻氧化应激，增加 DNMT1 表达水平以及 DNMT1 与 ATR 启动子区域的结合，从而降低 DMO 中 ATR、心率和 SBP 的 mRNA 和蛋白表达水平，但在 CMO 中没有降低。
本研究为妊娠糖尿病引起的后代高血压发病机制中交感神经系统过度活跃提供了证据。PVN 中的中枢抗氧化干预可能是胎儿编程性高血压的重要治疗策略。
