Angiopoietin-2 and vascular endothelial growth factor α inhibition by faricimab reduces pericyte-to-myofibroblast transition and the myofibroblast phenotype in vitro

Pericytes (PCs) are essential components of the retinal microvasculature and exhibit fibrotic activity, which is crucial for tissue repair and regeneration. However, chronic fibrotic activity can lead to harmful fibrosis that impairs retinal function. Treatment with faricimab, which targets angiopoietin-2 and vascular endothelial growth factor α (VEGFα) to prevent neovascularization in diabetic macular edema (DME), reduces epiretinal membrane (ERM) formation in DME, suggesting that faricimab has antifibrotic properties. Because PCs play an important role in fibrosis, we investigated the effects of faricimab on the pericyte-to-myofibroblast transition (PMT) in vitro. To induce PMT and generate myofibroblasts, primary human retinal PCs were treated with TGF-β1. Treatment with TGF-β1 reduced the VEGFα consumption of PCs in growth medium and increased the expression of α5β1 integrin, an angiopoietin-2 receptor. Interestingly, treatment with faricimab reduced the migratory capacity of PCs. Furthermore, faricimab treatment resulted in decreased levels of three fibrotic markers, fibronectin, F-actin, and α-smooth muscle actin (αSMA), during PMT and reduced fibronectin levels in transdifferentiated myofibroblasts. Inhibiting angiopoietin-2 and VEGFα decreased SMAD2 activity in myofibroblasts and increased total ERK 1/2 levels during PMT. In conclusion, faricimab reduced both PMT and myofibroblast activity in vitro. Although cell types other than PCs are also involved in retinal fibrosis, the inhibition of PC fibrotic activity by faricimab indicates that angiopoietin-2 and VEGFα play profibrotic roles in retinal diseases. These findings support the observation that patients with DME have reduced ERM formation after treatment with faricimab. Consequently, inhibiting angiopoietin-2 and VEGFα is a promising approach for modulating tissue fibrosis in retinal diseases and other conditions.