Opticin Ameliorates Hypoxia-Induced Retinal Angiogenesis by Suppression of Integrin α2-I Domain-Collagen Complex Formation and RhoA/ROCK1 Signaling.

Abstract

Purpose:

It was previously demonstrated that opticin (OPTC) inhibits the collagen-induced promotion of bioactivities of human retinal vascular endothelial cells (hRVECs). The present in vivo study aimed to further investigate the regulatory role of opticin in vitreous collagen-mediated retinal neovascularization and to elucidate its regulatory mechanisms with regard to integrin α2-I domain-GXXGER complex formation and RhoA/ROCK1 signal change. The regulatory role of Mg2+ on integrin α2-I domain-GXXGER complex formation in the above process was also investigated.

Methods:

The zebrafish model of hypoxia-induced retinopathy was established, and OPTC-overexpressing plasmids were intravitreally injected to assess the antiangiogenesis effect of opticin. The regulatory role of opticin in integrin α2-I domain-GXXGER complex formation in vivo was analyzed by mass spectrometry. The mRNA and protein expression of RhoA/ROCK1 were examined. The concentration of Mg2+ as an activator of the integrin α2-I domain-GXXGER complex was measured. Solid-phase binding assays were performed to investigate the interference of opticin in integrin α2 collagen binding and the regulatory role of Mg2+ in that process.

Results:

Opticin and OPTC-overexpressing plasmid injection reduced retinal neovascularization in the zebrafish model of hypoxia-induced retinopathy. Mass spectrometry revealed that opticin could inhibit integrin α2-I domain-GXXGER complex formation. The Mg2+ concentration was also decreased by opticin, which was another indication of the complex activation. Injection of OPTC-overexpressing plasmids inhibited mRNA and the protein expression of RhoA/ROCK1 in the zebrafish model of hypoxia-induced retinopathy. The solid-phase binding assay revealed that opticin could block integrin α2-collagen I binding in the presence of Mg2+.

Conclusions:

Opticin exerts its antiangiogenesis effect by interfering in the Mg2+-modulated integrin α2-I domain-collagen complex formation and suppressing the downstream RhoA/ ROCK1 signaling pathway.

• Authors: Xiaoxue Liu, Yue Xing, Xin Liu, Lingyan Zeng, Jin Ma
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 63 Issue 1 Pg. 13 (01 03 2022) ISSN: 1552-5783 [Electronic] United States
• PMID: 35006271 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Integrin alpha2
• Proteoglycans
• Zebrafish Proteins
• optc protein, zebrafish
• RNA
• ROCK1 protein, human
• rho-Associated Kinases
• Monomeric GTP-Binding Proteins
• rhoab protein, zebrafish

Topics

• Animals
• Disease Models, Animal
• Gene Expression Regulation
• Integrin alpha2 (biosynthesis, genetics)
• Monomeric GTP-Binding Proteins (biosynthesis, genetics)
• Proteoglycans (biosynthesis, genetics)
• RNA (genetics)
• Retinal Neovascularization (genetics, metabolism, pathology)
• Signal Transduction
• Zebrafish
• Zebrafish Proteins (biosynthesis, genetics)
• rho-Associated Kinases (biosynthesis, genetics)