Cysteine-rich 61, a member of the CCN family, as a factor involved in the pathogenesis of proliferative diabetic retinopathy.

Abstract

PURPOSE:

Cysteine-rich 61 (Cyr61/CCN1) is reported to mediate angiogenesis. In this study, its role in ocular angiogenesis and proliferative diabetic retinopathy (PDR) was investigated.

METHODS:

The effects of Cyr61 were evaluated by determining proliferation and chemotaxis and in an assay of capillary tube formation in synthetic matrix by chorioretinal endothelial cells (RF/6A). In the same cells, Cyr61 expression under hypoxic conditions was then investigated. Interactions between Cyr61 and vascular endothelial growth factor (VEGF) were examined using endothelial cell chemotaxis, tube-formation assay, and cross-stimulation assay. A mouse model of oxygen-induced retinopathy (OIR) and a rat model of streptozocin-induced diabetes were used to evaluate Cyr61 expression in the retina. Cyr61 levels were also measured and chemotactic effects were evaluated in vitreous samples from patients with PDR.

RESULTS:

Cyr61 significantly induced proliferation, migration, and synthetic matrix tube formation of RF/6A cells. Hypoxia significantly induced Cyr61 mRNA and protein expression. Cyr61 induced expression of VEGF and vice versa. Anti-Cyr61 or anti-VEGF could inhibit the effects of both Cyr61 and VEGF. Intravitreal injection of anti-Cyr61 antibody significantly inhibited retinal neovascularization in the mouse OIR model. Cyr61 mRNA and protein were significantly expressed in the retina of streptozocin-induced diabetic rats. Vitreous levels of Cyr61 were elevated in patients with PDR when compared with nondiabetic patients.

CONCLUSIONS:

Cyr61 acts as an angiogenic mediator of ocular neovascularization in vitro and in vivo. It may interact with VEGF in a synergetic manner. Vitreous levels of Cyr61 are elevated in PDR, and it may play an important role in the disease's pathogenesis.

• Authors: Jian-Jang You, Chang-Hao Yang, Muh-Shy Chen, Chung-May Yang
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 50 Issue 7 Pg. 3447-55 (Jul 2009) ISSN: 1552-5783 [Electronic] United States
• PMID: 19264885 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inducing Agents
• Cysteine-Rich Protein 61
• RNA, Messenger
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse
• vascular endothelial growth factor A, rat
• DNA

Topics

• Angiogenesis Inducing Agents (metabolism)
• Animals
• Blotting, Western
• Capillaries (physiology)
• Cell Culture Techniques
• Cell Movement
• Cell Proliferation
• Cysteine-Rich Protein 61 (physiology)
• DNA (biosynthesis)
• Diabetes Mellitus, Experimental (genetics)
• Diabetic Retinopathy (etiology, metabolism, pathology)
• Endothelium, Vascular (metabolism)
• Enzyme-Linked Immunosorbent Assay
• Gene Expression
• Humans
• Hypoxia (genetics)
• Infant, Newborn
• Luminescent Measurements
• Macaca mulatta
• Mice
• Mice, Inbred C57BL
• RNA, Messenger (metabolism)
• Rats
• Rats, Wistar
• Retinal Neovascularization (etiology, metabolism, pathology)
• Retinal Vessels (physiology)
• Retinopathy of Prematurity (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Vascular Endothelial Growth Factor A (metabolism)
• Vitreous Body (metabolism)