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

摘要 肥胖/超重患者发生认知障碍的风险增加，这可能导致 痴呆这是一个主要的公共卫生问题，因为大多数成年人超重或肥胖。 肥胖超重的人脑灌注减少，这可能导致认知受损; 这种脑灌注不足的原因尚不清楚。这是一个重要的知识差距;了解 低灌注的原因是确定治疗靶点以减缓或预防认知功能下降的关键。 肥胖困扰着社会。实质小动脉（PA）连接软脑膜和毛细血管网络， 调节脑实质的灌注。我们的初步数据显示内皮依赖性舒张 在来自超重大鼠的PA中显著受损，并且这些大鼠发展认知功能障碍。尽管他们 PA在调节脑灌注中的重要性，但对PA在健康和疾病中的功能知之甚少。PA扩张 在很大程度上依赖于细胞内钙（Ca 2+）信号传导和通过瞬时受体电位的Ca 2+内流 (TRP)通道是脑动脉内皮依赖性舒张的重要介质。我们发现 香草酸4 TRP通道（TRPV 4）的激活引起PA扩张。初步研究表明，TRPV 4 在超重大鼠中表达减少，这与盐皮质激素受体活化有关。循环 在超重患者和我们的大鼠和小鼠中， 模型我们的假设是PA内皮细胞中的MR激活导致TRPV 4表达减少， 内皮依赖性舒张功能受损、脑灌注不足和认知功能障碍。 我们将利用体内和体外技术的组合，包括MRI，共聚焦显微镜， 电生理学和压力肌描记术来验证我们的假设我们将确定过度肥胖 损害PA功能、脑灌注和认知。我们的工作假设是TRPV 4的表达是 在超重大鼠中减少，这导致受损的Ca 2+介导的内皮依赖性舒张， PA与脑灌注减少和认知受损有关。我们进一步建议， 抑制TRPV 4将导致脑灌注不足和认知能力下降。我们还将确定 MR激活对PA功能、脑灌注和认知的影响。我们的假设是， 在PA内皮细胞中引起TRPV 4表达减少，Ca 2+介导的扩张受损，脑血管内皮细胞受损， 灌注不足和认知能力下降。我们进一步提出，超重大鼠的MR拮抗作用将改善 PA以TRPV 4依赖性方式发挥功能，这将导致脑灌注和认知功能改善 功能MR是一个高度药物化的靶点，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大大减轻家庭和医疗保健的负担， 当患者的认知能力受损而无法独立生活时，就会出现这种情况。

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.