Stimulation of neovascularization by the anti-angiogenic factor PEDF
Rajendra S Apte1, Ramon A Barreiro, Elia Duh
1Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 S. Euclid, St. Louis, MO 63110, USA.
Purpose:
Examine the effect of (pigment epithelium-derived growth factor; PEDF) on laser-induced choroidal neovascularization (CNV).
Methods:
Adult C57Bl/6 mice were anesthetized and four laser spots were placed in each quadrant of the fundus with a krypton red laser (614 nm, 50 microm, 0.05 second, 200 mW). Animals were treated with various doses of PEDF administered with miniosmotic pumps implanted subcutaneously. Seven days after laser treatment, mice were perfused with 3% FITC high-molecular-weight dextran, the eyes enucleated, and neovascularization analyzed by confocal microscopy. Data were recorded as the volume of the neovascular complex. The effect of PEDF on endothelial cell migration, vascular tube formation in synthetic basement membrane, and VEGF production was also determined.
Results:
Mice receiving a lower dose of PEDF (90 microg/mL) had significantly decreased areas of CNV. A high dose of PEDF (360 microg/mL) significantly increased CNV, whereas an intermediate dose (180 microg/mL) of PEDF had no effect. PEDF inhibited endothelial cell migration and vascular tube formation at lower doses (0.5-5 microg/mL). High doses of PEDF (25-50 microg/mL) stimulated endothelial cell migration, enhanced vascular tube formation in vitro, and stimulated VEGF production from endothelial cells. Neutralizing anti-VEGF antibody completely reversed the stimulatory effects of high doses of PEDF on CNV in vivo.
Conclusions:
PEDF demonstrates opposing effects on CNV and endothelial cell function. Whereas low doses are inhibitory, high doses can augment the development of the neovasculature. These results suggest that the effects of PEDF on neovascularization are more complex than originally believed and that caution should be exercised when PEDF therapies are considered.
Insights
Pigment epithelium-derived growth factor (PEDF) has dual effects on choroidal neovascularization (CNV). Low PEDF doses inhibit CNV, while high doses promote its development, suggesting complex therapeutic considerations.
Area of Science:
- Ophthalmology
- Vascular Biology
- Molecular Medicine
Background:
- Choroidal neovascularization (CNV) is a major cause of vision loss.
- Pigment epithelium-derived growth factor (PEDF) is a secreted protein with potential roles in ocular diseases.
Purpose of the Study:
- To investigate the dose-dependent effects of PEDF on laser-induced CNV in a mouse model.
- To explore PEDF's impact on endothelial cell function and VEGF production.
Main Methods:
- Laser-induced CNV model in C57Bl/6 mice.
- Subcutaneous administration of varying PEDF doses via osmotic pumps.
- Confocal microscopy analysis of neovascular complex volume after FITC-dextran perfusion.
- In vitro assays for endothelial cell migration, vascular tube formation, and VEGF production.
Main Results:
- Low PEDF doses (90 microg/mL) significantly reduced CNV areas.
- High PEDF doses (360 microg/mL) significantly increased CNV.
- PEDF exhibited dose-dependent effects on endothelial cell migration and tube formation.
- High PEDF doses stimulated VEGF production, an effect reversed by anti-VEGF antibody.
Conclusions:
- PEDF demonstrates opposing effects on CNV development, acting as an inhibitor at low doses and a promoter at high doses.
- The complex, dose-dependent actions of PEDF on neovascularization warrant caution in therapeutic applications.
- PEDF's influence on endothelial cell behavior and VEGF signaling highlights its intricate role in vascular pathologies.
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