Girdin and its phosphorylation dynamically regulate neonatal vascular development and pathological neovascularization in the retina.

Abstract

Vascular endothelial growth factor (VEGF) is recognized as a principal mediator of vessel growth. VEGF regulates various endothelial cellular processes, including cell migration, proliferation, and survival, through the serine threonine protein kinase Akt. The Akt substrate girdin, an actin-binding protein, is known to regulate VEGF-mediated postnatal angiogenesis. However, the role of girdin and its phosphorylation in neonatal retinal vascular development and ocular pathological neovascularization in vivo has not been elucidated. In the present study, therefore, we investigated these processes using Girdin(+/-) mice lacking one copy of the girdin gene and girdin S1416A knockin (Girdin-KI(SA/SA)) mice in which the phosphorylation site of girdin is completely disrupted. We used three mouse models of pathological ocular neovascularization: oxygen-induced retinopathy (a mouse model of ischemic retinopathies), laser-induced choroidal neovascularization, and a human VEGF transgenic mouse that overexpresses human VEGF specifically in photoreceptor cells and generates pathological neovascularization in the retina. Neonatal vascular development was delayed and pathological neovascularization was decreased in both Girdin(+/-) mice and Girdin-KI(SA/SA) mice. These results demonstrate that girdin and its phosphorylation play an important role in neonatal vascular development and in pathological neovascularization in the retina.

• Authors: Takanori Ito, Keiichi Komeima, Tetsuhiro Yasuma, Atsushi Enomoto, Naoya Asai, Masato Asai, Sayoko Iwase, Masahide Takahashi, Hiroko Terasaki
• Journal: The American journal of pathology (Am J Pathol) Vol. 182 Issue 2 Pg. 586-96 (Feb 2013) ISSN: 1525-2191 [Electronic] United States
• PMID: 23195430 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• CCDC88A protein, human
• Chromones
• Microfilament Proteins
• Morpholines
• RNA, Messenger
• RNA, Small Interfering
• Vascular Endothelial Growth Factor A
• Vesicular Transport Proteins
• girdin protein, mouse
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Animals, Newborn
• Blood Vessels (drug effects, growth & development, metabolism)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Chromones (pharmacology)
• Disease Models, Animal
• Female
• Gene Knockdown Techniques
• Human Umbilical Vein Endothelial Cells (drug effects, metabolism)
• Humans
• Mice
• Microfilament Proteins (genetics, metabolism)
• Morpholines (pharmacology)
• Neovascularization, Physiologic (drug effects)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation (drug effects)
• Protein Transport (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Messenger (genetics, metabolism)
• RNA, Small Interfering (metabolism)
• Retina (drug effects, metabolism, pathology)
• Retinal Neovascularization (metabolism, pathology)
• Signal Transduction (drug effects)
• Vascular Endothelial Growth Factor A (metabolism)
• Vesicular Transport Proteins (genetics, metabolism)