Stern Javier E, Son Sookjin, Biancardi Vinicia C, Zheng Hong, Sharma Neeru, Patel Kaushik P
From the Department of Physiology, Augusta University, GA (J.E.S., S.S., V.C.B.); and Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (H.Z., N.S., K.P.P.).
Hypertension. 2016 Dec;68(6):1483-1493. doi: 10.1161/HYPERTENSIONAHA.116.07747. Epub 2016 Oct 3.
Angiotensin II (AngII) is a key neuropeptide that acting within the brain hypothalamic paraventricular nucleus regulates neurohumoral outflow to the circulation. Moreover, an exacerbated AngII action within the paraventricular nucleus contributes to neurohumoral activation in hypertension. Although AngII effects involve changes in paraventricular nucleus neuronal activity, the precise underlying mechanisms, cellular targets, and distribution of AngII receptors within the paraventricular nucleus remain largely unknown. Thus, whether AngII effects involve direct actions on paraventricular neurons, or whether it acts via intermediary cells, such as astrocytes, is still controversial. To address this important gap in our knowledge, we used a multidisciplinary approach combining patch-clamp electrophysiology in presympathetic paraventricular neurons and astrocytes, along with in vivo sympathetic nerve recordings and astrocyte-targeted gene manipulations. We present evidence for a novel mechanism underlying central AngII actions, which involves astrocytes as major intermediary cellular targets. We found that AngII type 1 receptor mRNA is expressed in paraventricular astrocytes. Moreover, we report that AngII inhibited glutamate transporter function, increasing in turn extracellular glutamate levels. This resulted in the activation of neuronal extrasynaptic NMDA (N-methyl-d-aspartate) receptors, increased presympathetic neuronal activity, enhanced sympathoexcitatory outflow, and increased blood pressure. Together, our studies support astrocytes as critical intermediary cell types mediating brain AngII regulation of the circulation and indicate that AngII-mediated neuronal and sympathoexcitatory effects are dependent on a unique neuroglial signaling modality involving nonsynaptic glutamate transmission.
血管紧张素 II（AngII）是一种关键的神经肽，其作用于脑下丘脑室旁核，调节神经体液向循环系统的输出。此外，室旁核内 AngII 作用的加剧会导致高血压中的神经体液激活。尽管 AngII 的作用涉及室旁核神经元活动的变化，但室旁核内确切的潜在机制、细胞靶点以及 AngII 受体的分布在很大程度上仍不清楚。因此，AngII 的作用是直接作用于室旁神经元，还是通过星形胶质细胞等中间细胞起作用，仍然存在争议。为了解决我们知识中的这一重要空白，我们采用了多学科方法，将交感神经节前室旁神经元和星形胶质细胞的膜片钳电生理学与体内交感神经记录以及星形胶质细胞靶向基因操作相结合。我们提供了中枢 AngII 作用的一种新机制的证据，该机制涉及星形胶质细胞作为主要的中间细胞靶点。我们发现 1 型 AngII 受体 mRNA 在室旁星形胶质细胞中表达。此外，我们报告 AngII 抑制了谷氨酸转运体功能，进而增加了细胞外谷氨酸水平。这导致神经元突触外 N-甲基-D-天冬氨酸（NMDA）受体激活、交感神经节前神经元活动增加、交感兴奋输出增强以及血压升高。总之，我们的研究支持星形胶质细胞作为介导脑 AngII 对循环系统调节的关键中间细胞类型，并表明 AngII 介导的神经元和交感兴奋作用依赖于一种独特的神经胶质信号传导方式，涉及非突触性谷氨酸传递。
