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Mice without uPA, tPA, or plasminogen genes are resistant to experimental choroidal neovascularization
Jean-Marie Rakic1, Vincent Lambert, Carine Munaut
1Department of Ophthalmology, University Hospital, Sart-Tilman, Liège, Belgium. jmrakic@chu.ulg.ac.be
Purpose:
To evaluate the presence and potential involvement of members of the plasminogen/plasminogen activator (Plg/PA) system in the exudative form of age-related macular degeneration (AMD).
Methods:
The expression of PA members mRNA was evaluated in human and experimental choroidal neovascularization (CNV) by RT-PCR. The presence and activity of PA was studied by immunofluorescence and in situ zymography. The influence of endogenous plasminogen (Plg), urokinase (uPA), tissue type plasminogen activator (tPA), and uPA receptor (uPAR) was explored in single-gene-deficient mice in a model of laser-induced CNV.
Results:
Members of the Plg/PA system were present both in human and murine CNV. The absence of Plg, uPA, or tPA significantly decreased the development of experimental CNV compared with wild-type or uPAR-deficient mice. This effect could be attributable, partly to a modulation of matrix metalloproteinase activity, but also to an accumulation of fibrinogen-fibrin in the laser-induced wounds.
Conclusions:
Together with previous work done by the authors, this study indicates that choroidal neovascularization is extremely sensitive to the modulation of Plg/PA system activity. This may provide a new strategy for the treatment of exudative AMD.
Insights
The plasminogen/plasminogen activator (Plg/PA) system is present in choroidal neovascularization (CNV). Inhibiting Plg/PA components reduced CNV development, suggesting a new treatment strategy for exudative age-related macular degeneration (AMD).
Area of Science:
- Ophthalmology
- Molecular Biology
- Biochemistry
Background:
- Age-related macular degeneration (AMD) is a leading cause of vision loss.
- Exudative AMD involves abnormal blood vessel growth (choroidal neovascularization, CNV).
- The role of the plasminogen/plasminogen activator (Plg/PA) system in CNV is not fully understood.
Purpose of the Study:
- To investigate the presence and function of the Plg/PA system in exudative AMD.
- To evaluate the impact of Plg/PA system components on choroidal neovascularization (CNV).
Main Methods:
- RT-PCR to assess mRNA expression of PA members in human and experimental CNV.
- Immunofluorescence and in situ zymography to detect PA presence and activity.
- Gene-deficient mice models (Plg, uPA, tPA, uPAR) to study CNV development after laser injury.
Main Results:
- Plg/PA system components were detected in both human and murine CNV.
- Absence of Plg, uPA, or tPA significantly reduced experimental CNV development.
- Reduced CNV was linked to modulated matrix metalloproteinase activity and fibrin accumulation.
Conclusions:
- The Plg/PA system plays a critical role in choroidal neovascularization.
- Modulating Plg/PA system activity shows promise for treating exudative AMD.
- This research opens new avenues for therapeutic strategies targeting AMD.