Propranolol Attenuates Proangiogenic Activity of Mononuclear Phagocytes: Implication in Choroidal Neovascularization
Samy Omri1, Houda Tahiri2, Wyston Chadwick Pierre3
1Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, Université de Montréal, Montreal, Quebec, Canada.
Insights
Propranolol reduces choroidal neovascularization (CNV) by enhancing antiangiogenic properties of macrophages. This effect is mediated by increased pigment epithelium-derived factor (PEDF) expression, suggesting propranolol as a potential therapy for CNV.
Area of Science:
- Ophthalmology
- Immunology
- Pharmacology
Background:
- Choroidal neovascularization (CNV) is a significant cause of vision loss.
- Macrophages play a critical role in the pathogenesis of CNV.
- The therapeutic potential of propranolol, a β-adrenergic receptor antagonist, in CNV is under investigation, particularly its effects on macrophages.
Purpose of the Study:
- To investigate the effect of propranolol on the angiogenic response of mononuclear phagocytes (MPs), a type of macrophage.
- To elucidate the mechanisms by which propranolol influences MP angiogenic properties.
Main Methods:
- Evaluation of propranolol's angiogenic effect in a laser-induced CNV mouse model.
- Assessment of CNV area and inflammatory cell infiltration using lectin staining and anti-IBA-1 antibody.
- Quantitative PCR analysis of inflammatory gene expression.
- In vitro studies using MP cell lines (J774, RAW264.7) and primary macrophages.
- Analysis of pro- and antiangiogenic mediators and pigment epithelium-derived factor (PEDF) expression.
Main Results:
- Propranolol treatment attenuated CNV and decreased inflammatory mediators IL-6 and TNFα.
- Macrophages (MPs) accumulated in the CNV area, but conditioned media from propranolol-treated MPs exhibited antiangiogenic effects.
- Propranolol increased pigment epithelium-derived factor (PEDF) expression in MPs.
- Blocking PEDF abrogated the antiangiogenic effects of propranolol.
Conclusions:
- Propranolol confers antiangiogenic properties on mononuclear phagocytes (MPs) by upregulating pigment epithelium-derived factor (PEDF) expression.
- This mechanism complements propranolol's direct effects on vascular tissue, inhibiting choroidal vasoproliferation.
- Propranolol shows promise as a therapeutic agent for choroidal neovascularization (CNV).
Purpose:
Targeting β-adrenergic receptor signaling with propranolol has emerged as a potential candidate to counteract choroidal neovascularization (CNV). Little is known of its effect on macrophages, which play a critical role in CNV. We investigated the effect of propranolol on angiogenic response of mononuclear phagocytes (MPs).
Methods:
The angiogenic effect of propranolol was evaluated in laser-induced CNV model. Mice received intraperitoneal injections of propranolol (6 mg/kg/d) or vehicle. CNV area and inflammatory cells were determined respectively by using lectin staining and an anti-IBA-1 antibody on RPE/choroid flat mounts. Inflammatory gene expression was evaluated by quantitative (q) PCR analysis. Mechanisms of propranolol was studied in MP cell lines J774 and RAW264.7 and in primary peritoneal macrophages. Expression of pro- and antiangiogenic mediators was studied. In addition, effects of propranolol treatment of MPs was assessed on choroidal explant.
Results:
CNV was attenuated by propranolol and concomitantly associated with decreased inflammatory mediators IL-6 and TNFα, albeit with accumulation of (β-adrenoceptor harboring) MPs in the CNV area. Conditioned media from MPs preincubated with propranolol exerted antiangiogenic effects. Treatment of J774 confirmed the attenuation of inflammatory response to propranolol and increased cleaved caspase-3 on choroidal explant. We found that propranolol increased pigment epithelium-derived factor (PEDF) expression in MPs. Trapping of PEDF with an antibody abrogated antiangiogenic effects of propranolol. PEDF was also detected in CNV-associated MPs.
Conclusions:
We hereby show that propranolol confers on MPs antiangiogenic properties by increasing PEDF expression, which complements its effects on vascular tissue resulting in inhibition of choroidal vasoproliferation in inflammatory conditions. The study supports possible use of propranolol as a therapeutic modality for CNV.
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