Kisler Kassandra, Nikolakopoulou Angeliki M, Sweeney Melanie D, Lazic Divna, Zhao Zhen, Zlokovic Berislav V
Department of Physiology and Neuroscience, The Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States.
Department of Neurobiology, Institute for Biological Research, University of Belgrade, Belgrade, Serbia.
Front Cell Neurosci. 2020 Feb 14;14:27. doi: 10.3389/fncel.2020.00027. eCollection 2020.
Pericytes are perivascular mural cells that enwrap brain capillaries and maintain blood-brain barrier (BBB) integrity. Most studies suggest that pericytes regulate cerebral blood flow (CBF) and oxygen delivery to activated brain structures, known as neurovascular coupling. While we have previously shown that congenital loss of pericytes leads over time to aberrant hemodynamic responses, the effects of acute global pericyte loss on neurovascular coupling have not been studied. To address this, we used our recently reported inducible pericyte-specific Cre mouse line crossed to iDTR mice carrying Cre-dependent human diphtheria toxin (DT) receptor, which upon DT treatment leads to acute pericyte ablation. As expected, DT led to rapid progressive loss of pericyte coverage of cortical capillaries up to 50% at 3 days post-DT, which correlated with approximately 50% reductions in stimulus-induced CBF responses measured with laser doppler flowmetry (LDF) and/or intrinsic optical signal (IOS) imaging. Endothelial response to acetylcholine, microvascular density, and neuronal evoked membrane potential responses remained, however, unchanged, as well as arteriolar smooth muscle cell (SMC) coverage and functional responses to adenosine, as we previously reported. Together, these data suggest that neurovascular uncoupling in this model is driven by pericyte loss, but not other vascular deficits or neuronal dysfunction. These results further support the role of pericytes in CBF regulation and may have implications for neurological conditions associated with rapid pericyte loss such as hypoperfusion and stroke, as well as conditions where the exact time course of global regional pericyte loss is less clear, such as Alzheimer's disease (AD) and other neurogenerative disorders.
周细胞是包绕脑毛细血管并维持血脑屏障（BBB）完整性的血管周围壁细胞。大多数研究表明，周细胞调节脑血流量（CBF）以及向被激活的脑结构输送氧气，即所谓的神经血管耦合。虽然我们之前已经表明，周细胞的先天性缺失会随着时间的推移导致异常的血流动力学反应，但急性全身性周细胞缺失对神经血管耦合的影响尚未得到研究。为了解决这个问题，我们使用了我们最近报道的可诱导的周细胞特异性Cre小鼠品系，与携带Cre依赖性人白喉毒素（DT）受体的iDTR小鼠杂交，DT处理后会导致周细胞急性消融。正如预期的那样，DT导致皮质毛细血管周细胞覆盖率在DT处理后3天迅速渐进性丧失，高达50%，这与用激光多普勒血流仪（LDF）和/或固有光信号（IOS）成像测量的刺激诱导的CBF反应降低约50%相关。然而，内皮细胞对乙酰胆碱的反应、微血管密度和神经元诱发的膜电位反应保持不变，小动脉平滑肌细胞（SMC）覆盖率以及对腺苷的功能反应也保持不变，正如我们之前报道的那样。总之，这些数据表明，该模型中的神经血管解耦是由周细胞丢失驱动的，而不是由其他血管缺陷或神经元功能障碍驱动的。这些结果进一步支持了周细胞在CBF调节中的作用，可能对与周细胞快速丢失相关的神经系统疾病（如灌注不足和中风）以及全球区域周细胞丢失的确切时间进程不太清楚的疾病（如阿尔茨海默病（AD）和其他神经退行性疾病）具有重要意义。
