Angiopoietin 2 induces pericyte apoptosis via α3β1 integrin signaling in diabetic retinopathy.
Pericyte loss is an early characteristic change in diabetic retinopathy (DR). Despite accumulating evidence that hyperglycemia-induced angiopoietin 2 (Ang2) has a central role in pericyte loss, the precise molecular mechanism has not been elucidated. This study investigated the role of Ang2 in pericyte loss in DR. We demonstrated that pericyte loss occurred with Ang2 increase in the diabetic mouse retina and that the source of Ang2 could be the endothelial cell. Ang2 induced pericyte apoptosis via the p53 pathway under high glucose, whereas Ang2 alone did not induce apoptosis. Integrin, not Tie-2 receptor, was involved for Ang2-induced pericyte apoptosis under high glucose as an Ang2 receptor. High glucose changed the integrin expression pattern, which increased integrin α3 and β1 in the pericyte. Furthermore, Ang2-induced pericyte apoptosis in vitro was effectively attenuated via p53 suppression by blocking integrin α3 and β1. Although intravitreal injection of Ang2 induced pericyte loss in C57BL/6J mice retina in vivo, intravitreal injection of anti-integrin α3 and β1 antibodies attenuated Ang2-induced pericyte loss. Taken together, Ang2 induced pericyte apoptosis under high glucose via α3β1 integrin. Glycemic control or blocking Ang2/integrin signaling could be a potential therapeutic target to prevent pericyte loss in early DR.
Fight against Angiogenesis-Related Blindness Laboratory, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea.
Sung Wook
SW
Park
Department of Pharmacology and Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul, Korea Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Korea.
Jang-Hyuk
JH
Yun
Fight against Angiogenesis-Related Blindness Laboratory, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
Jin Hyoung
JH
Kim
Department of Pharmacy, Seoul National University, Seoul, Korea.
Kyu-Won
KW
Kim
Department of Pharmacology and Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul, Korea Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Korea steph25@snu.ac.kr iamhyun@snu.ac.kr.
Chung-Hyun
CH
Cho
Fight against Angiogenesis-Related Blindness Laboratory, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea steph25@snu.ac.kr iamhyun@snu.ac.kr.
Jeong Hun
JH
Kim
D042702:Angiopoietin-2 / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D001813:Blood-Retinal Barrier / Q000502:physiology; D003930:Diabetic Retinopathy / Q000378:metabolism*; D005947:Glucose / Q000008:administration & dosage; D039201:Integrin alpha3beta1 / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology; D008297:Male; D051379:Mice; D020286:Pericytes / Q000378:metabolism*; D012160:Retina / Q000378:metabolism; D015398:Signal Transduction
D042702:Angiopoietin-2; D039201:Integrin alpha3beta1; D005947:Glucose