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JCI Insight. 2017 Feb 9;2(3):e90905. doi: 10.1172/jci.insight.90905.

Sustained inflammation after pericyte depletion induces irreversible blood-retina barrier breakdown.

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Department of Retinal Vascular Biology,; Department of Ophthalmology and Visual Sciences, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Department of Retinal Vascular Biology.
Department of Anatomy and Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Core Laboratory, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Laboratory of Veterinary Physiology, Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Iwate University, Morioka, Japan.
Graduate School of Nanoscience and Technology, and.
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
KAN Research Institute, Kobe, Japan.
Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.
Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan.
Faculty of Nursing, Hiroshima Bunka Gakuen University, Kure, Japan.
Department of Stem Cells and Human Disease Models, Research Center for Animal Life Science, Shiga University of Medical Science, Otsu, Japan.
Division of Vascular Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
Division of Phenotype Disease Analysis, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
Institute of Physiology and Medicine, Jobu University, Takasaki, Japan.
Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Department of Ophthalmology and Visual Sciences, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.


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-PDGFRβ 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.

Conflict of interest statement

W. Ikeda is an employee of the KAN Research Institute. H. Nara and H. Sakai are employees of Astellas Pharma Inc.

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