Angiopoietin 2 Induces Pericyte Apoptosis via α3β1 Integrin Signaling in Diabetic Retinopathy

  1. Jeong Hun Kim1,2,6,#,*
  1. 1Fight against Angiogenesis-Related Blindness Laboratory, Biomedical Research Institute, Seoul National University Hospital, Seoul 110-744, Korea
  2. 2Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Korea
  3. 3Department of Pharmacology and Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea
  4. 4Cancer Research Institute, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea
  5. 5Department of Pharmacy, Seoul National University, Seoul 151-742, Korea
  6. 6Department of Ophthalmology, Seoul National University Hospital, Seoul 110-744, Korea
  1. *Corresponding Author: Jeong Hun Kim, E-mail: steph25{at}snu.ac.kr
  1. S.W.P. and J.-H.Y. contributed equally to this work.

Abstract

Pericyte loss is an early characteristic change in diabetic retinopathy. Despite accumulating evidences that hyperglycemia induced angiopoietin 2 (Ang2) has a central role in pericyte loss, the precise molecular mechanism has not been elucidated. This study was to investigate the role of Ang2 in pericyte loss in diabetic retinopathy. We demonstrated that pericyte loss occurred with Ang2 increase in the diabetic mice retina, and the source of Ang2 could be endothelial cell. Ang2 induced pericyte apoptosis via p53 pathway under high glucose while 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 integrin expression pattern which increased integrin α3 and β1 in pericyte. Furthermore, in vitro, Ang2 induced pericyte apoptosis was effectively attenuated via p53 suppression by blocking integrin α3 and β1. In vivo, while intravitreal injection of Ang2 induced pericyte loss in C57/BL6 mice retina, 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 diabetic retinopathy.

Footnotes

  • # These authors are regarded as co-corresponding authors.

  • Received December 24, 2013.
  • Accepted March 30, 2014.

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This Article

  1. Diabetes