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Updated: Jul 12, 2026
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Published on: June 30, 2023
Positive feedback regulation between MMP-9 and VEGF in human RPE cells
Margrit Hollborn1, Christina Stathopoulos, Anja Steffen
1Department of Ophthalmology and Eye Clinic, University of Leipzig Faculty of Medicine, Leipzig, Germany. hollbm@medizin.uni-leipzig.de
Purpose:
The proteolytic activity of matrix metalloproteinases (MMPs) is involved in pathologic angiogenesis in the eye. However, it is unknown whether MMPs may stimulate the production of the major angiogenic factor, vascular endothelial growth factor (VEGF). The authors investigated whether MMP-2 and MMP-9 alter the expression of VEGF by retinal pigment epithelial (RPE) cells. They also sought to determine the effects of MMPs on cellular proliferation and migration and the effect of triamcinolone acetonide on MMP-9-evoked cellular responses.
Methods:
Human RPE cell cultures were stimulated with MMP-2 or MMP-9. The gene expression and secretion of MMP-9 and VEGF were determined by real-time RT-PCR and ELISA, respectively. Cellular proliferation was investigated with a bromodeoxyuridine immunoassay, and chemotaxis was examined with a Boyden chamber assay.
Results:
Under control conditions, RPE cells in vitro expressed a significantly higher amount of mRNA for MMP-2 than for MMP-9. Chemical hypoxia caused upregulation of the gene expression of both MMPs, whereas VEGF increased the gene expression and secretion of MMP-9. The hypoxic expression of MMP-9 was mediated by autocrine VEGF signaling. Exogenous MMP-9 increased the gene expression and secretion of VEGF, whereas MMP-2 reduced the secretion of VEGF. MMP-2 and MMP-9 did not alter the proliferation but stimulated the migration of RPE cells. Triamcinolone fully inhibited the stimulatory effect of MMP-9 on the expression of VEGF and the VEGF-evoked increase in the expression of MMP-9. However, triamcinolone had no effect on the motogenic effect of MMP-9.
Conclusions:
There is a positive feedback regulation between MMP-9 and VEGF in RPE cells. The hypoxic expression of MMP-9 may stimulate the production and secretion of VEGF under pathologic conditions. Triamcinolone inhibits the positive feedback regulation between MMP-9 and VEGF under hypoxic conditions through inhibition of the gene expression of MMP-9 and the secretion of VEGF.
Insights
Matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) have a positive feedback loop in retinal pigment epithelial cells. Triamcinolone acetonide inhibits this MMP-9 and VEGF interaction, potentially impacting eye diseases.
Area of Science:
- Ophthalmology
- Molecular Biology
- Cell Biology
Background:
- Proteolytic activity of matrix metalloproteinases (MMPs) contributes to pathologic angiogenesis in the eye.
- The role of MMPs in stimulating vascular endothelial growth factor (VEGF) production remains unclear.
Purpose of the Study:
- To investigate if MMP-2 and MMP-9 alter VEGF expression in retinal pigment epithelial (RPE) cells.
- To determine the effects of MMPs on RPE cell proliferation and migration.
- To assess the impact of triamcinolone acetonide on MMP-9-induced cellular responses.
Main Methods:
- Human RPE cells were stimulated with MMP-2 or MMP-9.
- Gene expression and secretion of MMP-9 and VEGF were quantified using real-time RT-PCR and ELISA.
- Cellular proliferation and migration were assessed via bromodeoxyuridine immunoassay and Boyden chamber assay, respectively.
Main Results:
- Hypoxia upregulated MMP-2 and MMP-9 gene expression in RPE cells, mediated by autocrine VEGF signaling.
- MMP-9 increased VEGF gene expression and secretion, while MMP-2 reduced VEGF secretion.
- MMP-2 and MMP-9 stimulated RPE cell migration but not proliferation.
- Triamcinolone acetonide inhibited MMP-9-induced VEGF expression and secretion, and the VEGF-evoked increase in MMP-9 expression, but not MMP-9's effect on migration.
Conclusions:
- A positive feedback loop exists between MMP-9 and VEGF in RPE cells.
- Hypoxic MMP-9 expression may drive VEGF production in pathologic eye conditions.
- Triamcinolone acetonide disrupts this MMP-9/VEGF feedback loop under hypoxia by inhibiting gene expression and secretion.
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