Cysteine-rich 61, a member of the CCN family, as a factor involved in the pathogenesis of proliferative diabetic retinopathy.
OBJECTIVE
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.
You
Jian-Jang
JJ
Department of Ophthalmology, Keelung General Hospital, Keelung, Taiwan.
Yang
Chang-Hao
CH
Chen
Muh-Shy
MS
Yang
Chung-May
CM
D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002196:Capillaries / Q000502:physiology; D018929:Cell Culture Techniques; D002465:Cell Movement; D049109:Cell Proliferation; D055515:Cysteine-Rich Protein 61 / Q000502:physiology*; D004247:DNA / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000235:genetics; D003930:Diabetic Retinopathy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D006801:Humans; D000860:Hypoxia / Q000235:genetics; D007231:Infant, Newborn; D008163:Luminescent Measurements; D008253:Macaca mulatta; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015861:Retinal Neovascularization / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012171:Retinal Vessels / Q000502:physiology; D012178:Retinopathy of Prematurity / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014822:Vitreous Body / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D055515:Cysteine-Rich Protein 61; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C467498:vascular endothelial growth factor A, rat; D004247:DNA