Neuroimmune mechanisms underlying electroacupuncture effect on vascular function

项目总结 高血压(HTN)是心血管疾病最重要的可改变的危险因素，涉及多个途径，包括神经内分泌和免疫系统。抗高血压药物可以治疗HTN，但不涉及中枢交感神经和炎症通路，大约50%的高血压(HTNive)患者无法控制血压(BP)。世界卫生组织曾建议针灸治疗HTN；然而，先前利用针灸进行的临床试验显示，疗效不佳或无效，并未取得临床上有意义的降压效果。这些相互矛盾的结果是由于缺乏一种基于机械的方法来使用电针(EA)，电针是一种神经刺激形式。治疗不充分和血压控制不充分的原因很复杂，但这种治疗错位的原因之一可能是对HTN发生和发展的潜在机制不完全了解，包括自主神经功能障碍和由此导致的低级别炎症。利用神经解剖图谱、表型分析和神经生理反应记录，我们成功地选择了与电针潜在的神经调节机制相对应的特定穴位，这些穴位联合(或联合(C)电针)表现出交感抑制和副交感兴奋的互补机制，不仅将血压降低到有临床意义的水平，而且还改善了潜在的自主神经功能障碍和低级别炎症。我们提出的研究解决了NCCIH的首要任务之一，“确定和分析针灸发挥其治疗效果的神经路径。”我们来自Dahl盐敏感(DSS)HTNive大鼠的强大初步数据表明，我们的靶穴同时激活正中、胫骨和腓深神经的传入，然后通过激活孤束核(NTS)、迷走神经背核(DMV)中的神经元来调节中枢神经系统的调节。这种调节导致下降的外周副交感神经脾活动增加。CEA治疗也降低了交感前神经元和内脏交感神经的活动。在这项研究中，我们将研究CEA治疗是否通过改善自主神经功能障碍和通过我们初步发现的神经机制途径减少炎症来降低血压。我们的主要目的是评估CEA在HTNive动物身上的降压作用机制，然后通过将其翻译到轻中度HTNive患者身上来验证其对自主神经指数的改善。我们计划通过以下方式实现这一目标：1)直接评估CEA对控制交感和副交感神经平衡的下丘脑和脑干区神经元的影响，包括NTS、DMV、室旁核和延髓头端腹外侧区，以及交感和副交感神经传出活动；2)研究CEA是否通过乙酰胆碱能受体(AChR)活性在DSS HTNive大鼠中减轻炎症；3)在一项人类随机对照研究中，采用平行的2x2因子设计，主要评估CEA与Sham-EA的比较(以及次要比较交感抑制电针、抗炎电针和CEA)对自主功能的生理调节和对慢性炎症的继发性影响。如果成功，这项研究将解决电针作为HTNive患者的一种治疗选择的效果的机制基础，这些患者仅用传统治疗并不能达到最佳的血压目标。

PROJECT SUMMARY Hypertension (HTN) is the most significant modifiable risk factor for cardiovascular disease and involves multiple pathways including those in the neuroendocrine and immune systems. Antihypertensive drugs manage HTN but do not address the central sympathetic and inflammatory pathways and approximately 50% of hypertensive (HTNive) patients do not have their blood pressure (BP) controlled. The World Health Organization has suggested acupuncture for HTN; however, prior clinical trials utilizing acupuncture have shown modest or null outcomes and not achieved clinically meaningful reductions in BP. These conflicting outcomes result from the lack of a mechanistic-based approach to using electroacupuncture (EA), a form of neurostimulation. The reasons for inadequate treatment and BP control are complex, but one reason for this therapeutic misalignment may be an incomplete understanding of the mechanisms underlying the development and progression of HTN including autonomic dysfunction and resulting low-grade inflammation. Using neuroanatomical mapping, phenotyping, and recording of neurophysiological responses that correspond to neuromodulatory mechanisms underlying effects of EA, we successfully selected specific acupoints that in combination (or combined (c)EA) show complementary mechanisms of sympathoinhibition and parasympathoexcitation and not only reduce BP to clinically meaningful levels but also improve underlying autonomic dysfunction and low-grade inflammation. Our proposed study addresses one of NCCIH’s top priorities, “Determine and analyze the neural pathways by which acupuncture exerts its therapeutic effects.” Our strong preliminary data, from Dahl Salt Sensitive (DSS) HTNive rats, show that our targeted acupoints, which simultaneously activate afferents in the median, tibial, and deep peroneal nerves then modulate CNS regulation by activation of neurons in the nucleus of tractus solitarius (NTS), dorsal motor nucleus of the vagus (DMV). This modulation resulted in an increase in descending peripheral parasympathetic splenic activity. Treatment with cEA also reduced presympathetic neuronal and splanchnic sympathetic nerve activities. In this study, we will investigate if cEA treatment leads to BP reduction by improving autonomic dysfunction and decreasing inflammation through the neural mechanistic pathways we have preliminarily discovered. Our main aim is to assess mechanisms of the BP lowering effect of cEA in HTNive animals and then validate the improvement in autonomic indices by translating it in mild-moderative HTNive patients. We plan to achieve this by: 1) direct assessment of the effect of cEA on neurons in the hypothalamic and brainstem regions controlling sympathetic and parasympathetic balance including NTS, DMV, paraventricular nucleus, and rostral ventrolateral medulla, as well as sympathetic and parasympathetic efferent activities; 2) investigating if cEA reduces inflammation through acetylcholinergic receptors (AChR) activity in DSS HTNive rats; and 3) using a parallel 2x2 factorial design in a human randomized control study, primarily assess effects of cEA compared to sham-EA (as well as secondarily compare sympathoinhibitory-EA, anti-inflammatory-EA, and cEA) on physiological alterations in autonomic function and secondarily on chronic inflammation. If successful, this study would address the mechanistic basis for the effects of EA as a therapeutic option for HTNive patients who are not at optimal BP goals with conventional therapy alone.