Regional early and progressive loss of brain pericytes but not vascular smooth muscle cells in adult mice with disrupted platelet-derived growth factor receptor-β signaling.
Regional early and progressive loss of brain pericytes but not vascular smooth muscle cells in adult mice with disrupted platelet-derived growth factor receptor-β signaling.
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DOI：
10.1371/journal.pone.0176225
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Zlokovic BV
中科院分区：
文献类型：
--
作者：
Nikolakopoulou AM;Zhao Z;Montagne A;Zlokovic BV
周细胞调节大脑的关键神经血管功能。对周细胞缺陷转基因小鼠进行的研究有助于更好地了解周细胞在大脑中的作用，这些转基因小鼠的周细胞中内皮源性血小板源性生长因子 BB (PDGF-BB) 和血小板源性生长因子受体 β (PDGFRβ) 之间存在异常信号传导。在这里，我们研究了 PdgfrβF7/F7 小鼠，它们携带七个点突变，破坏 PDGFRβ 信号传导，导致发育中大脑中周细胞和血管平滑肌细胞 (VSMC) 的损失。我们询问这些小鼠出生后是否具有稳定或渐进的血管表型，以及成年大脑中的周细胞和 VSMC 群是否都受到影响。我们发现早期和进行性的区域依赖性大脑周细胞损失、微血管减少和血脑屏障（BBB）破坏，这些在皮质、海马和纹状体中比丘脑中更为明显，而在周细胞损失已经确定时，VSMCs群仍然不受影响。例如，与年龄匹配的对照相比，4-6周龄和36-48周龄的PdgfrβF7/F7小鼠出现了区域依赖性周细胞覆盖度（22-46、24-44和4-31%）和细胞数量（36-49、34-64和11-36%）的损失，毛细血管长度减少（20-39、13-46和11-36%）。 1-30%），血管外纤维蛋白原沉积物增加（3.4-5.2、2.8-4.1 和 0-3.6 倍），分别表明皮质、海马和丘脑的 BBB 破裂。毛细血管减少和血脑屏障破坏与周细胞覆盖范围的丧失相关。我们的数据表明，PdgfrβF7/F7 小鼠在没有明显早期 VSMC 参与的情况下形成了一种侵袭性和快速的血管表型，因此为研究周细胞损失对脑血管和神经元功能的区域影响提供了一个有价值的模型。该模型可能成为未来研究的有用工具，旨在了解周细胞在与周细胞损失相关的神经系统疾病（如血管性痴呆、阿尔茨海默病、肌萎缩侧索硬化症、中风和人类免疫缺陷病毒相关神经认知障碍）发病机制中的作用。
Pericytes regulate key neurovascular functions of the brain. Studies in pericyte-deficient transgenic mice with aberrant signaling between endothelial-derived platelet-derived growth factor BB (PDGF-BB) and platelet-derived growth factor receptor β (PDGFRβ) in pericytes have contributed to better understanding of the role of pericytes in the brain. Here, we studied PdgfrβF7/F7 mice, which carry seven point mutations that disrupt PDGFRβ signaling causing loss of pericytes and vascular smooth muscle cells (VSMCs) in the developing brain. We asked whether these mice have a stable or progressive vascular phenotype after birth, and whether both pericyte and VSMCs populations are affected in the adult brain. We found an early and progressive region-dependent loss of brain pericytes, microvascular reductions and blood-brain barrier (BBB) breakdown, which were more pronounced in the cortex, hippocampus and striatum than in the thalamus, whereas VSMCs population remained unaffected at the time when pericyte loss was already established. For example, compared to age-matched controls, PdgfrβF7/F7 mice between 4–6 and 36–48 weeks of age developed a region-dependent loss in pericyte coverage (22–46, 24–44 and 4–31%) and cell numbers (36–49, 34–64 and 11–36%), reduction in capillary length (20–39, 13–46 and 1–30%), and an increase in extravascular fibrinogen-derived deposits (3.4–5.2, 2.8–4.1 and 0–3.6-fold) demonstrating BBB breakdown in the cortex, hippocampus and thalamus, respectively. Capillary reductions and BBB breakdown correlated with loss of pericyte coverage. Our data suggest that PdgfrβF7/F7 mice develop an aggressive and rapid vascular phenotype without appreciable early involvement of VSMCs, therefore providing a valuable model to study regional effects of pericyte loss on brain vascular and neuronal functions. This model could be a useful tool for future studies directed at understanding the role of pericytes in the pathogenesis of neurological disorders associated with pericyte loss such as vascular dementia, Alzheimer’s disease, amyotrophic lateral sclerosis, stroke and human immunodeficiency virus-associated neurocognitive disorder.