BACKGROUND Whether maternal hypertension contributes to the enhanced susceptibility to vascular remodeling in adult offspring through epigenetic mechanisms remains unclear. We aimed to address this gap in the literature using a transgenerational mouse model. METHODS Gestational hypertension was induced in pregnant mice using chronic angiotensin II infusion. Blood pressure was monitored using the tail-cuff method. Two months post-delivery, an N6-methyladenosine epitranscriptomic microarray analysis was performed on the carotid arteries of second-generation mice. A unilateral carotid artery injury model was used to study the postinjury vascular response in vivo. Furthermore, carotid ultrasonography, immunohistochemistry, and molecular biological parameters were assessed in adult offspring. RESULTS Exposure to maternal hypertension decreased the birth weight of live pups and increased the fetal death rate. Compared with normal offspring, adult offspring with hypertension had wire-induced injury that led to greater vascular remodeling, which was associated with aggravated inflammation imbalance, fibrosis, and oxidative stress. In addition, aberrant N6-methyladenosine methylation, increased N6-methyladenosine levels, and increased METTL3 (methyltransferase-like 3) expression were detected in the vessels of offspring with hypertension. Maternal METTL3 deficiency increased the birth weight of live pups with hypertension, improved vascular dysfunction, and alleviated vascular inflammation in adult offspring with hypertension after injury. CONCLUSIONS Maternal hypertension can induce transgenerational transmission of enhanced susceptibility to vascular remodeling, and the possible underlying mechanism is associated with altered METTL3-mediated N6-methyladenosine methylation. Therefore, this study reveals the role of epigenetic effects across generations and provides new insights into vascular remodeling causes.

中文翻译：

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母体高血压通过 N6-甲基腺苷的跨代传递加重雄性成年后代受伤后的血管功能障碍。


背景 母体高血压是否通过表观遗传机制导致成年后代对血管重塑的易感性增强尚不清楚。我们旨在使用跨代小鼠模型来解决文献中的这一空白。方法 使用慢性血管紧张素 II 输注诱导妊娠小鼠妊娠高血压。使用尾袖方法监测血压。分娩后 2 个月，对第二代小鼠的颈动脉进行 N6-甲基腺苷表观转录组微阵列分析。单侧颈动脉损伤模型用于研究体内损伤后血管反应。此外，还评估了成年后代的颈动脉超声检查、免疫组化和分子生物学参数。结果 暴露于母体高血压降低了活仔的出生体重并增加了胎儿死亡率。与正常后代相比，患有高血压的成年后代有钢导的损伤，导致更大的血管重塑，这与加重的炎症失衡、纤维化和氧化应激有关。此外，在高血压后代的血管中检测到异常的 N6-甲基腺苷甲基化、N6-甲基腺苷水平升高和 METTL3 （甲基转移酶样 3） 表达增加。母体 METTL3 缺乏增加了高血压活仔的出生体重，改善了血管功能障碍，并减轻了受伤后成年高血压后代的血管炎症。结论 母体高血压可诱导血管重塑易感性增强的跨代传递，可能的潜在机制与 METTL3 介导的 N6-甲基腺苷甲基化改变有关。 因此，本研究揭示了表观遗传效应跨代的作用，并为血管重塑原因提供了新的见解。