Wang Yaoming, Kisler Kassandra, Nikolakopoulou Angeliki Maria, Fernandez Jose A, Griffin John H, Zlokovic Berislav V
Department of Physiology and Neuroscience, Keck School of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, United States.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, United States.
Front Neurosci. 2022 Mar 30;16:841916. doi: 10.3389/fnins.2022.841916. eCollection 2022.
Pericytes, mural cells of brain capillaries, maintain the blood-brain barrier (BBB), regulate cerebral blood flow (CBF), and protect neurons against ischemic damage. To further investigate the role of pericytes in ischemia, we induced stroke by 45-min transient middle cerebral artery occlusion (tMCAo) in 6-month-old pericyte-deficient mice and control littermates. Compared to controls, mice showed a 26% greater loss of CBF during early reperfusion, and 40-50% increase in the infarct and edema volumes and motor neurological score 24 h after tMCAo. These changes were accompanied by 50% increase in both immunoglobulin G and fibrinogen pericapillary deposits in the ischemic cortex 8 h after tMCAo indicating an accelerated BBB breakdown, and 35 and 55% greater losses of pericyte coverage and number of degenerating neurons 24 h after tMCAo, respectively. Treatment of mice with 3K3A-activated protein C (APC), a cell-signaling analog of plasma protease APC, administered intravenously 10 min and 4 h after tMCAo normalized CBF during the early reperfusion phase and reduced infarct and edema volume and motor neurological score by 55-60%, with similar reductions in BBB breakdown and number of degenerating neurons. Our data suggest that pericyte deficiency results in greater brain injury, BBB breakdown, and neuronal degeneration in stroked mice and that 3K3A-APC protects the brain from accelerated injury caused by pericyte deficiency. These findings may have implications for treatment of ischemic brain injury in neurological conditions associated with pericyte loss such as those seen during normal aging and in neurodegenerative disorders such as Alzheimer's disease.
周细胞是脑毛细血管的壁细胞，维持血脑屏障（BBB），调节脑血流量（CBF），并保护神经元免受缺血性损伤。为了进一步研究周细胞在缺血中的作用，我们通过对6个月大的周细胞缺陷小鼠和对照同窝小鼠进行45分钟的短暂大脑中动脉闭塞（tMCAo）来诱导中风。与对照组相比，周细胞缺陷小鼠在早期再灌注期间CBF损失增加了26%，在tMCAo后24小时梗死体积、水肿体积和运动神经学评分增加了40 - 50%。这些变化伴随着tMCAo后8小时缺血皮层中免疫球蛋白G和纤维蛋白原毛细血管周围沉积物增加50%，表明血脑屏障加速破坏，以及tMCAo后24小时周细胞覆盖损失增加35%和变性神经元数量增加55%。在tMCAo后10分钟和4小时静脉注射3K3A活化蛋白C（APC，血浆蛋白酶APC的细胞信号类似物）对周细胞缺陷小鼠进行治疗，可使早期再灌注阶段的CBF恢复正常，并使梗死体积、水肿体积和运动神经学评分降低55 - 60%，血脑屏障破坏和变性神经元数量也有类似程度的降低。我们的数据表明，周细胞缺陷导致中风小鼠脑损伤加重、血脑屏障破坏和神经元变性，而3K3A - APC可保护大脑免受周细胞缺陷引起的加速损伤。这些发现可能对与周细胞丢失相关的神经疾病（如正常衰老过程中所见以及阿尔茨海默病等神经退行性疾病）中的缺血性脑损伤治疗具有启示意义。
