Sustained inflammation after pericyte depletion induces irreversible blood-retina barrier breakdown
Sustained inflammation after pericyte depletion induces irreversible blood-retina barrier breakdown
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DOI：
10.1172/jci.insight.90905
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发表时间：
2017-02-09
期刊：
影响因子：
8
通讯作者：
Uemura, Akiyoshi
中科院分区：
文献类型：
--
作者：
Ogura, Shuntaro;Kurata, Kaori;Uemura, Akiyoshi
在中枢神经系统中，血管壁的内皮细胞（EC）和周细胞（PC）共同形成一个物理和化学屏障，以维持神经内稳态。然而，在糖尿病视网膜病变（DR）中，PC从血管壁的损失被认为会导致血视网膜屏障（BRB）的破坏和随后的威胁视力的血管功能障碍。尽管如此，缺乏足够的DR动物模型已经排除了疾病的理解和药物的发现。在这里，通过使用抗PDGFR β抗体，我们表明，短暂抑制PC招聘到发展中的视网膜血管持续EC-PC解离和BRB分解在成年小鼠视网膜，再现DR的特征，如高渗透性，低灌注，和新生血管形成。值得注意的是，PC耗竭直接诱导EC中的炎症反应和巨噬细胞的血管周围浸润，由此巨噬细胞衍生的VEGF和胎盘生长因子（PlGF）激活巨噬细胞中的VEGFR 1和EC中的VEGFR 2。此外，血管生成素2（Angpt 2）上调和Tie 1下调激活FOXO 1在PC无EC局部泄漏动脉瘤。通过同时阻断VEGF、PlGF和Angpt 2来关闭这种血管损伤循环，从而恢复BRB的完整性。总之，我们的模型提供了新的机会，识别PC缺陷引发的连续事件，不仅在DR，而且在各种神经系统疾病。
In the central nervous system, endothelial cells (ECs) and pericytes (PCs) of blood vessel walls cooperatively form a physical and chemical barrier to maintain neural homeostasis. However, in diabetic retinopathy (DR), the loss of PCs from vessel walls is assumed to cause breakdown of the blood-retina barrier (BRB) and subsequent vision-threatening vascular dysfunctions. Nonetheless, the lack of adequate DR animal models has precluded disease understanding and drug discovery. Here, by using an anti-PDGFR beta antibody, we show that transient inhibition of the PC recruitment to developing retinal vessels sustained EC-PC dissociations and BRB breakdown in adult mouse retinas, reproducing characteristic features of DR such as hyperpermeability, hypoperfusion, and neoangiogenesis. Notably, PC depletion directly induced inflammatory responses in ECs and perivascular infiltration of macrophages, whereby macrophage-derived VEGF and placental growth factor (PlGF) activated VEGFR1 in macrophages and VEGFR2 in ECs. Moreover, angiopoietin-2 (Angpt2) upregulation and Tie1 downregulation activated FOXO1 in PC-free ECs locally at the leaky aneurysms. This cycle of vessel damage was shut down by simultaneously blocking VEGF, PlGF, and Angpt2, thus restoring the BRB integrity. Together, our model provides new opportunities for identifying the sequential events triggered by PC deficiency, not only in DR, but also in various neurological disorders.