Propranolol Attenuates Proangiogenic Activity of Mononuclear Phagocytes: Implication in Choroidal Neovascularization

Abstract

Targeting b-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 TNFa, albeit with accumulation of (b-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.

Macrophage-derived interleukin-6 is necessary and sufficient for choroidal angiogenesis

“…IL6 is increased after laser injury (Fig. 1 ), and reduced by propranolol 3 , 4 . We next investigated whether IL6 is necessary for propranolol-driven CNV blockade.…”

“…Our group, and several other labs, have demonstrated that beta-adrenergic receptor blockade inhibits experimental CNV by 50–80% 3 – 8 . These findings led to a randomized, placebo controlled clinical trial.…”

“…Interleukin-6 (IL6) is a pro-inflammatory cytokine produced by macrophages. Classical monocyte-derived macrophages are necessary for propranolol-driven CNV blockade 6 , and propranolol decreases IL6 levels during experimental CNV 3 , 4 . These data implicate macrophage-derived IL6 as a key driver of experimental CNV.…”

Blocking Ocular Sympathetic Activity Inhibits Choroidal Neovascularization

“…Though no studies have investigated the effect of β-AR agonists on the progression of laser-induced CNV, several studies in mice have reported that systemic or intraocular delivery of β-AR antagonists causes a reduction in CNV lesion size ( Lavine et al, 2013 , 2017 ; Nourinia et al, 2015 ; Omri et al, 2019 ). Lavine et al (2013) measured lesion areas (as opposed to volumes) 14 days after laser photocoagulation and found that daily intraperitoneal injection of propranolol (20 mg/kg/day) led to a 50% reduction in lesion size.…”

Role of LINC01592 in TGF-β1-induced epithelial-mesenchymal transition of retinal pigment epithelial cells

“…Moreover, studies have shown that lncRNA plays an important role in triggering EMT in epithelial cells during tumor metastasis [ 14 , 15 ]. MALAT1 can promote the proliferation, migration, and epiretinal membrane formation of RPE cells in PVR [ 16 , 17 ]. In addition, it was confirmed that downregulation of MALAT1 could inhibit the induction of EMT by TGF-β1 in ARPE-19 cells, and significantly reduced the upregulation of EMT-related transcription factors Snail, SLUG, and ZEB1 in RPE cells [ 18 , 19 ].…”