title: Sustained inflammation after pericyte depletion induces irreversible blood-retina barrier breakdown.
abstract: 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.
authors.affiliation: Department of Retinal Vascular Biology.|Department of Ophthalmology and Visual Sciences, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Ogura
authors.affiliation: Department of Retinal Vascular Biology.
authors.forename: Kaori
authors.initials: K
authors.lastname: Kurata
authors.affiliation: Department of Anatomy and Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hattori
authors.affiliation: Core Laboratory, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takase
authors.affiliation: Laboratory of Veterinary Physiology, Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Iwate University, Morioka, Japan.
authors.forename: Toshina
authors.initials: T
authors.lastname: Ishiguro-Oonuma
authors.affiliation: Graduate School of Nanoscience and Technology, and.
authors.forename: Yoonha
authors.initials: Y
authors.lastname: Hwang
authors.affiliation: Graduate School of Nanoscience and Technology, and.
authors.forename: Soyeon
authors.initials: S
authors.lastname: Ahn
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Inwon
authors.initials: I
authors.lastname: Park
authors.affiliation: KAN Research Institute, Kobe, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Ikeda
authors.affiliation: Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Sentaro
authors.initials: S
authors.lastname: Kusuhara
authors.affiliation: Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Fukushima
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nara
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan.
authors.forename: Hideto
authors.initials: H
authors.lastname: Sakai
authors.affiliation: Faculty of Nursing, Hiroshima Bunka Gakuen University, Kure, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Department of Stem Cells and Human Disease Models, Research Center for Animal Life Science, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Matsushita
authors.affiliation: Department of Stem Cells and Human Disease Models, Research Center for Animal Life Science, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Ema
authors.affiliation: Division of Vascular Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Hirashima
authors.affiliation: Division of Phenotype Disease Analysis, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Minami
authors.affiliation: Institute of Physiology and Medicine, Jobu University, Takasaki, Japan.
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.affiliation: Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takakura
authors.affiliation: Graduate School of Nanoscience and Technology, and.
authors.forename: Pilhan
authors.initials: P
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Takaki
authors.initials: T
authors.lastname: Miyata
authors.affiliation: Department of Ophthalmology and Visual Sciences, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ogura
authors.affiliation: Department of Retinal Vascular Biology.|Department of Ophthalmology and Visual Sciences, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Uemura
mesh_terms: D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D001813:Blood-Retinal Barrier; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000276:immunology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008565:Membrane Proteins; D051379:Mice; D020286:Pericytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042702:Angiopoietin-2; D000906:Antibodies; D008565:Membrane Proteins; C490827:Pigf protein, mouse; D011506:Proteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D020797:Receptor, Platelet-Derived Growth Factor beta