Cerebrovascular Smooth Muscle Cells as the Drivers of Intramural Periarterial Drainage of the Brain
Cerebrovascular Smooth Muscle Cells as the Drivers of Intramural Periarterial Drainage of the Brain
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DOI：
10.3389/fnagi.2019.00001
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发表时间：
2019-01-23
影响因子：
4.8
通讯作者：
Richardson, Giles
中科院分区：
文献类型：
--
作者：
Aldea, Roxana;Weller, Roy O.;Richardson, Giles
人类大脑是代谢活动最高的器官，但它缺乏负责清除废物的传统淋巴系统。我们已经证明，脑毛细血管和动脉的基底膜代表了脑的淋巴通路，可溶性代谢物的壁内动脉周围引流（iPad）沿着该通路发生。iPad的失败可以将淀粉样β蛋白的血管沉积解释为脑淀粉样血管病（CAA），这是阿尔茨海默病的关键病理特征。iPad的潜在机制，包括其动力，尚未阐明，延迟了CAA的成功治疗。虽然心脏的动脉搏动最初被认为是iPad的动力，但它们对于高效的iPad来说还不够强大。这项研究旨在通过将心脏驱动的可溶性代谢物从大脑中清除的观点转移到脑动脉的内在机制（例如，血管运动驱动的iPad）。我们测试的假设，脑血管平滑肌细胞，其周期的收缩和舒张产生血管运动，是iPad的驱动程序。一种新的多尺度模型的动脉，在其中，我们处理的基底膜作为一个充满流体的多孔弹性介质变形的收缩脑血管平滑肌细胞，是用来检验这一假设。血管舒缩诱导的壁内流速表明，血管舒缩驱动的iPad是迄今为止能够解释现有实验观察结果的唯一机制。脑血管平滑肌细胞可能是预防和早期干预CAA的有价值的药物靶点。
The human brain is the organ with the highest metabolic activity but it lacks a traditional lymphatic system responsible for clearing waste products. We have demonstrated that the basement membranes of cerebral capillaries and arteries represent the lymphatic pathways of the brain along which intramural periarterial drainage (IPAD) of soluble metabolites occurs. Failure of IPAD could explain the vascular deposition of the amyloid-beta protein as cerebral amyloid angiopathy (CAA), which is a key pathological feature of Alzheimer's disease. The underlying mechanisms of IPAD, including its motive force, have not been clarified, delaying successful therapies for CAA. Although arterial pulsations from the heart were initially considered to be the motive force for IPAD, they are not strong enough for efficient IPAD. This study aims to unravel the driving force for IPAD, by shifting the perspective of a heart-driven clearance of soluble metabolites from the brain to an intrinsic mechanism of cerebral arteries (e.g., vasomotion-driven IPAD). We test the hypothesis that the cerebrovascular smooth muscle cells, whose cycles of contraction and relaxation generate vasomotion, are the drivers of IPAD. A novel multiscale model of arteries, in which we treat the basement membrane as a fluid-filled poroelastic medium deformed by the contractile cerebrovascular smooth muscle cells, is used to test the hypothesis. The vasomotion-induced intramural flow rates suggest that vasomotion-driven IPAD is the only mechanism postulated to date capable of explaining the available experimental observations. The cerebrovascular smooth muscle cells could represent valuable drug targets for prevention and early interventions in CAA.