Related Experiment Video
Updated: Mar 8, 2026
Monitoring Dynamic Growth of Retinal Vessels in Oxygen-Induced Retinopathy Mouse Model
Published on: April 2, 2021
IGF-1R Regulates the Extracellular Level of Active MMP-2, Pathological Neovascularization, and Functionality in
Valeria E Lorenc1,2, Paula V Subirada Caldarone1, María C Paz1
1Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
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.
Insights
The insulin-like growth factor 1 (IGF-1) system regulates active matrix metalloproteinase-2 (MMP-2) in Müller glial cells (MGCs). This finding offers new insights into treating neovascular diseases like retinopathy.
Area of Science:
- Ophthalmology
- Cell Biology
- Molecular Biology
Background:
- Ischemic retinopathies involve neovascularization driven by hypoxia.
- Matrix metalloproteinases (MMPs), specifically MMP-2 and MMP-9, are crucial in abnormal blood vessel formation.
- The role of insulin-like growth factor 1 (IGF-1) and its receptor (IGF-1R) in neovascularization is complex.
Purpose of the Study:
- To investigate the role of MMP-2 from Müller glial cells (MGCs) in retinopathy.
- To explore the relationship between MMP-2 and the IGF-1/IGF-1R system in MGCs.
- To assess the therapeutic potential of blocking IGF-1R in a mouse model of retinopathy.
Main Methods:
- Utilized an oxygen-induced retinopathy (OIR) mouse model and an in vitro hypoxia model.
- Analyzed MMP-2 expression in retinal tissues and MGCs.
- Administered an IGF-1R blocking antibody (αIR3) intravitreally.
- Assessed retinal neovascularization, revascularization, and function.
Main Results:
- MMP-2 protein expression increased in OIR mice during active neovascularization.
- MMP-2 and IGF-1R were localized to MGCs.
- IGF-1R blockade prevented pathologic neovascularization and improved retinal function.
- IGF-1R blockade inhibited IGF-1-induced active MMP-2 in MGCs.
Conclusions:
- The IGF-1/IGF-1R system is a key regulator of active MMP-2 in MGCs.
- This interaction contributes to retinal neovascularization in retinopathy.
- Targeting the IGF-1/IGF-1R system may offer a therapeutic strategy for ischemic proliferative diseases.
