Cheng Yiming, Ma Xiaotang, Belfield Kevin D, Haorah James
Laboratory of Neurovascular Inflammation and Neurodegeneration, Department of Biomedical Engineering, Center for Injury Bio Mechanics, Materials and Medicine, New Jersey Institute of Technology, Newark, NJ, 07102, USA.
Department of Chemistry and Environmental Science, College of Science and Liberal Arts, New Jersey Institute of Technology, 323 Martin Luther King, Jr., Blvd., Newark, NJ, 07102, USA.
Mol Neurobiol. 2021 Aug;58(8):3953-3967. doi: 10.1007/s12035-021-02379-w. Epub 2021 Apr 25.
We have shown that the effects of low-dose ethanol promote the clearance of waste metabolites, such as amyloid-beta (Aβ) proteins, from the brain through the perivascular space (PVS). We demonstrated that dilative reactivity of arterial smooth muscle and endothelial cells regulate this clearance. These findings indicate the importance of blood-brain barrier (BBB) transvascular clearance of large size metabolites from the central nervous system (CNS), where the lymphatic clearance system is absent. We next examined the contrasting effects of acute low-dose and chronic moderate ethanol exposure on BBB-associated perivascular clearance. We injected a high molecular weight fluorescent dye into the interstitial space or directly into the cerebrospinal fluid (CSF). Bio-distribution of this tracer was then examined in different brain regions by multiphoton imaging and whole brain tissue section scanning. Ethanol-induced molecular/cellular mechanisms that drive the increase or decrease in movement of the fluorescent tracer were correlated to BBB integrity and arterial vessel reactivity. We found that activation of endothelial nitric oxide synthase (eNOS) under low-dose ethanol conditions with a shift to activation of inducible NOS (iNOS) under chronic high ethanol exposure conditions, which appeared to regulate these contrasting effects. We validated these observations by qualitative and quantitative investigation of eNOS, iNOS, BBB integrity, and perivascular clearance of waste metabolites. We concluded that the effects of low-dose ethanol increased the diffusive movement of waste metabolites via eNOS-derived NO, which increased the arterial endothelial-smooth muscle cell dilative reactivity without affecting BBB integrity, whereas a prolonged induction of iNOS under chronic ethanol exposure conditions caused oxidative damage of the arterial endothelial-smooth muscle layers resulting in cerebral amyloid-like angiopathy. This led to dysfunction of the BBB, dilative reactivity, and impaired waste metabolites movement from the interstitial space or subarachnoid space (SAS) through perivascular clearance.
我们已经表明，低剂量乙醇的作用可促进脑内废物代谢产物（如β-淀粉样蛋白（Aβ））通过血管周围间隙（PVS）从大脑中清除。我们证明动脉平滑肌和内皮细胞的舒张反应性调节这种清除。这些发现表明，在缺乏淋巴清除系统的中枢神经系统（CNS）中，血脑屏障（BBB）对大尺寸代谢产物的跨血管清除具有重要意义。接下来，我们研究了急性低剂量和慢性中度乙醇暴露对与BBB相关的血管周围清除的对比作用。我们将一种高分子量荧光染料注入间质空间或直接注入脑脊液（CSF）。然后通过多光子成像和全脑组织切片扫描检查该示踪剂在不同脑区的生物分布。乙醇诱导的驱动荧光示踪剂移动增加或减少的分子/细胞机制与BBB完整性和动脉血管反应性相关。我们发现，在低剂量乙醇条件下内皮型一氧化氮合酶（eNOS）被激活，而在慢性高乙醇暴露条件下诱导型一氧化氮合酶（iNOS）被激活，这似乎调节了这些对比作用。我们通过对eNOS、iNOS、BBB完整性和废物代谢产物的血管周围清除进行定性和定量研究，验证了这些观察结果。我们得出结论，低剂量乙醇的作用通过eNOS衍生的NO增加了废物代谢产物的扩散运动，这增加了动脉内皮-平滑肌细胞的舒张反应性，而不影响BBB完整性，而在慢性乙醇暴露条件下iNOS的长期诱导导致动脉内皮-平滑肌层的氧化损伤，从而导致脑淀粉样血管病。这导致BBB功能障碍、舒张反应性受损以及废物代谢产物从间质空间或蛛网膜下腔（SAS）通过血管周围清除的运动受损。
