Cerebral parenchymal arteriole dysfunction and cognitive decline in a life-long high fat feeding model

摘要 肥胖/超重患者患认知障碍的风险增加，这可能导致 痴呆症。这是一个重大的公共卫生问题，因为大多数成年人口超重或 太胖了。超重的人大脑灌注量减少，这会导致认知障碍； 这种脑低灌注症的原因尚不清楚。这是一个重要的知识鸿沟；理解 低灌流的原因是确定治疗靶点以减缓或防止认知功能下降的关键 饱受肥胖困扰的社会。实质小动脉(PA)连接软膜和毛细血管网络， 调节脑实质的灌注量。我们的初步数据显示，内皮依赖性扩张 在超重大鼠的PAS中明显受损，这些大鼠出现认知功能障碍。尽管他们 由于PA在调节脑血流中的重要性，人们对PA在健康和疾病中的作用知之甚少。PAS中的扩张性 严重依赖于细胞内钙(Ca~(2+))信号，钙离子通过瞬时受体电位内流 色氨酸(Trp)通道是脑动脉内皮依赖性扩张的重要介质。我们向大家展示了 激活香草素-4-色氨酸通道(TRPV4)可引起PA扩张。初步研究表明，TRPV4 在超重的大鼠中表达减少，这与盐皮质激素受体的激活有关。流通中 超重患者以及我们的大鼠和小鼠体内的盐皮质激素醛固酮水平升高 模特们。我们的假设是，PA内皮细胞中MR的激活导致TRPV4表达减少， 超重大鼠的内皮依赖性扩张、脑低灌流和认知损害。 我们将利用体内和体外技术的组合，包括磁共振成像、共聚焦显微镜、 电生理学和压力肌电图来验证我们的假设。我们将确定过度肥胖是如何 损害PA功能、脑灌注和认知。我们的工作假设是TRPV4的表达是 超重大鼠的降低，这导致钙离子介导的内皮依赖性舒张功能受损。 PAS与脑血流减少和认知受损有关。我们进一步建议直接 抑制TRPV4会导致脑灌流不足和认知功能下降。我们还将确定 MR激活对PA功能、脑血流灌注和认知的影响。我们的工作假设是MR激活 在PA内皮细胞中导致TRPV4表达减少，损害钙离子介导的扩张，脑 低灌注率和认知能力下降。我们进一步提出，超重大鼠的MR拮抗作用将得到改善。 PA的功能依赖于TRPV4，这将导致改善脑血流灌注和认知能力 功能。MR是一个高度可用药的靶点，MR拮抗剂是FDA批准的安全、有效的药物。他们的 在超重/肥胖人群中使用可以显著减轻家庭和医疗保健的负担 当患者的认知损伤太严重而无法独立生活时发生的一种系统。

Abstract Obese/overweight patients have an increased risk of developing cognitive impairments that can lead to dementia. This is a major public health concern because the majority of the adult population is overweight or obese. Overweight individuals have reduced cerebral perfusion and this can cause impaired cognition; the cause of this cerebral hypoperfusion is unknown. This is an important knowledge gap; understanding the cause of the hypoperfusion is key to identifying therapeutic targets to slow or prevent cognitive decline in a society plagued by obesity. The parenchymal arterioles (PAs) connect the pial and capillary networks and regulate the perfusion of the brain parenchyma. Our preliminary data show that endothelium dependent dilation is markedly impaired in PAs from overweight rats and these rats develop cognitive dysfunction. Despite their importance in regulating brain perfusion, little is known about PA function in health and disease. Dilation in PAs relies heavily on intracellular calcium (Ca2+) signaling, and Ca2+ influx through transient receptor potential (TRP) channels is an important mediator of cerebral artery endothelium dependent dilation. We showed that activation of the vanilloid 4 TRP channel (TRPV4) causes PA dilation. Preliminary studies show that TRPV4 expression is reduced in overweight rats and this is linked to mineralocorticoid receptor activation. Circulating levels of the mineralocorticoid aldosterone are increased in overweight patients and in our rat and mouse models. Our hypothesis is that MR activation in PA endothelial cells leads to reduced TRPV4 expression, impaired endothelium-dependent dilation, cerebral hypoperfusion and cognitive impairment in overweight rats. We will utilize a combination of in vivo and in vitro techniques including MRI, confocal microscopy, electrophysiology and pressure myography to test our hypothesis. We will determine how excess adiposity impairs PA function, cerebral perfusion, and cognition. Our working hypothesis is that TRPV4 expression is reduced in overweight rats and that this leads to impaired Ca2+-mediated endothelium-dependent dilation in PAs and is associated with reduced cerebral perfusion and impaired cognition. We further propose that directly inhibiting TRPV4 will cause cerebral hypoperfusion and cognitive decline. We will also determine the effects of MR activation on PA function, cerebral perfusion, and cognition. Our working hypothesis is that MR activation in PA endothelial cells causes reduced TRPV4 expression, impaired Ca2+ mediated dilation, cerebral hypoperfusion and cognitive decline. We further propose that MR antagonism in overweight rats will improve PA function in a TRPV4 dependent manner and that this will lead to improved cerebral perfusion and cognitive function. The MR is a highly drugable target, MR antagonists are safe, effective FDA approved drugs. Their use in the overweight/obese population could dramatically reduce the burden on families and the healthcare system that occurs when patients become too cognitively impaired to live independently.