Abstract:
Neurogenic hypertension stems from an imbalance in autonomic function that shifts the central cardiovascular control circuits toward a state of dysfunction. Using the female spontaneously hypertensive rat and the normotensive Wistar-Kyoto rat model, we compared the transcriptomic changes in three autonomic nuclei in the brainstem, nucleus of the solitary tract (NTS), caudal ventrolateral medulla, and rostral ventrolateral medulla (RVLM) in a time series at 8, 10, 12, 16, and 24 wk of age, spanning the prehypertensive stage through extended chronic hypertension. RNA-sequencing data were analyzed using an unbiased, dynamic pattern-based approach that uncovered dominant and several subtle differential gene regulatory signatures. Our results showed a persistent dysregulation across all three autonomic nuclei regardless of the stage of hypertension development as well as a cascade of transient dysregulation beginning in the RVLM at the prehypertensive stage that shifts toward the NTS at the hypertension onset. Genes that were persistently dysregulated were heavily enriched for immunological processes such as antigen processing and presentation, the adaptive immune response, and the complement system. Genes with transient dysregulation were also largely region-specific and were annotated for processes that influence neuronal excitability such as synaptic vesicle release, neurotransmitter transport, and an array of neuropeptides and ion channels. Our results demonstrate that neurogenic hypertension is characterized by brainstem region-specific transcriptomic changes that are highly dynamic with significant gene regulatory changes occurring at the hypertension onset as a key time window for dysregulation of homeostatic processes across the autonomic control circuits.NEW & NOTEWORTHY Hypertension is a major disease and is the primary risk factor for cardiovascular complications and stroke. The gene expression changes in the central nervous system circuits driving hypertension are understudied. Here, we show that coordinated and region-specific gene expression changes occur in the brainstem autonomic circuits over time during the development of a high blood pressure phenotype in a rat model of human essential hypertension.
摘要:
神经性高血压源于自主神经功能的不平衡,使中枢心血管控制回路转向功能障碍状态。利用雌性自发性高血压大鼠(SHR)和血压正常的WistarKyoto(WKY)大鼠模型,我们比较了脑干中三个自主神经核的转录变化,孤束核(NTS),尾端腹外侧延髓(CVLM),在8、10、12、16和24周龄的时间序列中和延髓腹外侧(RVLM),通过延长的慢性高血压跨越高血压前期阶段。RNAseq数据使用无偏分析,基于动态模式的方法,揭示了一个显性和几个微妙的差异基因调控特征。我们的结果显示,无论高血压的发展阶段如何,所有三个自主神经核都存在持续的失调,以及在高血压前期的RVLM中开始的短暂失调的级联反应,在高血压发作时向NTS转移。持续失调的基因大量富集用于免疫过程,如抗原加工和呈递,适应性免疫反应,和补充系统。短暂性失调的基因在很大程度上也是区域特异性的,并被注释为影响神经元兴奋性的过程,如突触小泡释放,神经递质运输,以及一系列神经肽和离子通道。我们的结果表明,神经源性高血压的特征是脑干区域特异性转录组变化,这种变化是高度动态的,在高血压发作时发生的显着基因调节变化是自主神经控制电路中稳态过程失调的关键时间窗口。