Growth factors outside the PDGF family drive experimental PVR
Hetian Lei1, Gisela Velez, Peter Hovland
1Department of Ophthalmology, Harvard Medical School, Schepens Eye Research Institute, Boston, Massachusetts 02114, USA.
Purpose:
Proliferative vitreoretinopathy (PVR) is a recurring and problematic disease for which there is no pharmacologic treatment. Platelet-derived growth factor (PDGF) in the vitreous is associated with experimental and clinical PVR. Furthermore, PDGF receptors (PDGFRs) are present and activated in epiretinal membranes of patient donors, and they are essential for experimental PVR. These observations suggest that PVR arises at least in part from PDGF/PDGFR-driven events. The goal of this study was to determine whether PDGFs were a potential therapeutic target for PVR.
Methods:
Experimental PVR was induced in rabbits by injecting fibroblasts. Vitreous specimens were collected from experimental rabbits or from patients undergoing vitrectomy to repair retinal detachment. A neutralizing PDGF antibody and a PDGF Trap were tested for their ability to prevent experimental PVR. Activation of PDGFR was monitored by antiphosphotyrosine Western blot analysis of immunoprecipitated PDGFRs. Contraction of collagen gels was monitored in vitro.
Results:
Neutralizing vitreal PDGFs did not effectively attenuate PVR, even though the reagents used potently blocked PDGF-dependent activation of the PDGF alpha receptor (PDGFRalpha). Vitreal growth factors outside the PDGF family modestly activated PDGFRalpha and appeared to do so without engaging the ligand-binding domain of PDGFRalpha. This indirect route to activate PDGFRalpha had profound functional consequences. It promoted the contraction of collagen gels and appeared sufficient to drive experimental PVR.
Conclusions:
Although PDGF appears to be a poor therapeutic target, PDGFRalpha is particularly attractive because it can be activated by a much larger spectrum of vitreal growth factors than previously appreciated.
Insights
Platelet-derived growth factor (PDGF) did not effectively treat proliferative vitreoretinopathy (PVR). However, PDGF alpha receptor (PDGFRalpha) activation by other factors suggests it is a promising therapeutic target for PVR.
Area of Science:
- Ophthalmology
- Regenerative Medicine
- Molecular Biology
Background:
- Proliferative vitreoretinopathy (PVR) is a recurrent condition lacking effective pharmacological treatments.
- Platelet-derived growth factor (PDGF) and its receptors (PDGFRs) are implicated in PVR pathogenesis.
- PDGFRs are present and activated in epiretinal membranes from patients with PVR.
Purpose of the Study:
- To investigate PDGF as a potential therapeutic target for PVR.
- To determine the role of PDGF/PDGFR signaling in experimental PVR.
Main Methods:
- Experimental PVR was induced in rabbits.
- Vitreous samples were analyzed from rabbits and human patients.
- Neutralizing PDGF antibody and PDGF Trap were used to block PDGF.
- PDGFR activation was assessed via Western blot.
- Collagen gel contraction was monitored in vitro.
Main Results:
- Neutralizing PDGF did not significantly reduce experimental PVR.
- PDGFRalpha was activated by non-PDGF vitreal growth factors.
- Indirect PDGFRalpha activation promoted collagen gel contraction and PVR.
- PDGFRalpha activation occurred independently of the PDGF ligand-binding domain.
Conclusions:
- PDGF is not an ideal therapeutic target for PVR.
- PDGFRalpha is a promising therapeutic target due to its activation by diverse vitreal factors.
- Targeting PDGFRalpha may offer a novel strategy for PVR treatment.
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