Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065.
Harold and Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York 10065.
J Neurosci. 2021 Feb 10;41(6):1349-1362. doi: 10.1523/JNEUROSCI.2360-19.2020. Epub 2020 Dec 10.
There are significant neurogenic and inflammatory influences on blood pressure, yet the role played by each of these processes in the development of hypertension is unclear. Tumor necrosis factor α (TNFα) has emerged as a critical modulator of blood pressure and neural plasticity; however, the mechanism by which TNFα signaling contributes to the development of hypertension is uncertain. We present evidence that following angiotensin II (AngII) infusion the TNFα type 1 receptor (TNFR1) plays a key role in heightened glutamate signaling in the hypothalamic paraventricular nucleus (PVN), a key central coordinator of blood pressure control. Fourteen day administration of a slow-pressor dose of AngII in male mice was associated with transcriptional and post-transcriptional (increased plasma membrane affiliation) regulation of TNFR1 in the PVN. Further, TNFR1 was shown to be critical for elevated NMDA-mediated excitatory currents in sympathoexcitatory PVN neurons following AngII infusion. Finally, silencing PVN TNFR1 prevented the increase in systolic blood pressure induced by AngII. These findings indicate that TNFR1 modulates a cellular pathway involving an increase in NMDA-mediated currents in the PVN following AngII infusion, suggesting a mechanism whereby TNFR1 activation contributes to hypertension via heightened hypothalamic glutamate-dependent signaling. Inflammation is critical for the emergence of hypertension, yet the mechanisms by which inflammatory mediators contribute to this dysfunction are not clearly defined. We show that tumor necrosis factor α receptor 1 (TNFR1) in the paraventricular hypothalamic nucleus (PVN), a critical neuroregulator of cardiovascular function, plays an important role in the development of hypertension in mice. In the PVN, TNFR1 expression and plasma membrane localization are upregulated during hypertension induced by angiotensin II (AngII). Further, TNFR1 activation was essential for NMDA signaling and the heightening NMDA currents during hypertension. Finally, TNFR1 silencing in the PVN inhibits elevated blood pressure induced by AngII. These results point to a critical role for hypothalamic TNFR1 signaling in hypertension.
有重要的神经和炎症对血压的影响，但这些过程中的每一个在高血压的发展中所起的作用尚不清楚。肿瘤坏死因子-α（TNFα）已经成为血压和神经可塑性的关键调节剂；然而，TNFα信号转导在高血压发展中的作用机制尚不确定。我们提出的证据表明，血管紧张素 II（AngII）输注后，肿瘤坏死因子-α 1 型受体（TNFR1）在下丘脑室旁核（PVN）中谷氨酸信号的增强中起着关键作用，PVN 是血压控制的关键中枢协调器。在雄性小鼠中，给予慢性降压剂量的 AngII 14 天，与 PVN 中 TNFR1 的转录和转录后（增加质膜亲和力）调节有关。此外，TNFR1 对于 AngII 输注后 PVN 中的交感兴奋性神经元中升高的 NMDA 介导的兴奋性电流是至关重要的。最后，沉默 PVN TNFR1 可防止 AngII 引起的收缩压升高。这些发现表明，TNFR1 调节了一种细胞途径，该途径涉及 AngII 输注后 PVN 中 NMDA 介导的电流增加，这表明 TNFR1 激活通过增强下丘脑谷氨酸依赖性信号转导导致高血压的一种机制。炎症对于高血压的发生至关重要，但是炎症介质导致这种功能障碍的机制尚不清楚。我们表明，肿瘤坏死因子-α受体 1（TNFR1）在下丘脑室旁核（PVN）中，心血管功能的关键神经调节剂，在小鼠高血压的发展中起着重要作用。在 PVN 中，TNFR1 的表达和质膜定位在血管紧张素 II（AngII）诱导的高血压期间上调。此外，TNFR1 激活对于 NMDA 信号和高血压期间 NMDA 电流的增强是必需的。最后，PVN 中的 TNFR1 沉默抑制 AngII 引起的血压升高。这些结果表明，下丘脑 TNFR1 信号在高血压中起着关键作用。
