title: IGF-1R Regulates the Extracellular Level of Active MMP-2, Pathological Neovascularization, and Functionality in Retinas of OIR Mouse Model.
abstract: In ischemic proliferative diseases such as retinopathies, persistent hypoxia leads to the release of numerous neovascular factors that participate in the formation of abnormal vessels and eventually cause blindness. The upregulation and activation of metalloproteinases (MMP-2 and MMP-9) represent a final common pathway in this process. Although many regulators of the neovascular process have been identified, the complete role of the insulin-like growth factor 1 (IGF-1) and its receptor (IGF-1R) appears to be significantly more complex. In this study, we used an oxygen-induced retinopathy (OIR) mouse model as well as an in vitro model of hypoxia to study the role of MMP-2 derived from Müller glial cells (MGCs) and its relation with the IGF-1/IGF-1R system. We demonstrated that MMP-2 protein expression increased in P17 OIR mice, which coincided with the active phase of the neovascular process. Also, glutamine synthetase (GS)-positive cells were also positive for MMP-2, whereas IGF-1R was expressed by GFAP-positive cells, indicating that both proteins were expressed in MGCs. In addition, in the OIR model a single intravitreal injection of the IGF-1R blocking antibody (αIR3) administered at P12 effectively prevented pathologic neovascularization, accelerated physiological revascularization, and improved retinal functionality at P17. Finally, in MGC supernatants, the blocking antibody abolished the IGF-1 effect on active MMP-2 under normoxic and hypoxic conditions without affecting the extracellular levels of pro-MMP-2. These results demonstrate, for the first time, that the IGF-1/IGF-1R system regulates active MMP-2 levels in MGCs, thus contributing to MEC remodeling during the retinal neovascular process.
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.|The Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Valeria E
authors.initials: VE
authors.lastname: Lorenc
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Paula V
authors.initials: PV
authors.lastname: Subirada Caldarone
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: María C
authors.initials: MC
authors.lastname: Paz
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Darío G
authors.initials: DG
authors.lastname: Ferrer
authors.affiliation: Centro Privado de Ojos Romagosa-Fundación VER, Córdoba, Argentina.
authors.forename: José D
authors.initials: JD
authors.lastname: Luna
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Chiabrando
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina. csanchez@fcq.unc.edu.ar.
authors.forename: María C
authors.initials: MC
authors.lastname: Sánchez
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D063928:Ependymoglial Cells / Q000378:metabolism / Q000473:pathology; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D010100:Oxygen; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D015861:Retinal Neovascularization / Q000209:etiology / Q000378:metabolism* / Q000473:pathology
chemical_list: D017526:Receptor, IGF Type 1; D020778:Matrix Metalloproteinase 2; D005974:Glutamate-Ammonia Ligase; D010100:Oxygen
keywords: Hypoxia; IGF-1R; IGF-1R blocking antibody αIR3; Matrix metalloproteinases; Müller glial cell; Oxygen-induced retinopathy