Neuroimmune mechanisms underlying electroacupuncture effect on vascular function

项目摘要 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。 抗高血压药物可以控制HTN，但不能解决中枢交感神经和炎症通路，大约50%的高血压（HTNive）患者的血压（BP）没有得到控制。 世界卫生组织建议针灸治疗HTN;然而，以前的临床试验利用针灸显示适度或无效的结果，并没有实现临床上有意义的血压降低。这些相互矛盾的结果是由于缺乏使用电针（EA）（一种神经刺激形式）的机械方法。治疗和血压控制不充分的原因很复杂，但这种治疗不一致的原因之一可能是对HTN发展和进展的机制的不完全理解，包括自主神经功能障碍和导致的低度炎症。 使用神经解剖学映射、表型分析和记录对应于EA作用的神经调节机制的神经生理反应，我们成功地选择了特定的穴位，这些穴位组合（或组合（c）EA）显示出交感神经抑制和副交感神经兴奋的互补机制，不仅将BP降低到临床有意义的水平，而且还改善了潜在的自主神经功能障碍和低度炎症。 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作用的神经通路。” 我们来自Dahl盐敏感（DSS）HTNive大鼠的强有力的初步数据表明，我们的靶向穴位同时激活正中神经、胫神经和腓深神经中的传入，然后通过激活孤束核（NTS）、迷走神经背侧运动核（DMV）中的神经元来调节CNS调节。 这种调制导致下降外周副交感神经脾脏活动的增加。 用cEA处理还减少了前交感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治疗是否通过我们初步发现的神经机制途径改善自主神经功能障碍和减少炎症来降低血压。 我们的主要目的是评估cEA在HTNive动物中降低血压作用的机制，然后通过在轻度-中度HTNive患者中转换来验证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对控制交感神经和副交感神经平衡的下丘脑和脑干区域（包括NTS、DMV、室旁核和延髓头端腹外侧区）中的神经元以及交感神经和副交感神经传出活动的影响; 2）研究cEA是否通过DSS HTNive大鼠中的乙酰胆碱能受体（AChR）活性减轻炎症;和3）在人类随机对照研究中使用平行2 × 2析因设计，主要评估cEA与假EA相比（以及其次比较交感神经兴奋性EA、抗炎性EA和cEA）对自主神经功能的生理改变的影响，其次评估对慢性炎症的影响。如果成功的话，这项研究将解决EA作为HTNive患者治疗选择的机制基础，这些患者单独使用常规治疗无法达到最佳BP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.