Senescent retinal pigment epithelial cells promote angiogenesis in choroidal neovascularization via the TAK1/p38 MAPK pathway

Senescent retinal pigment epithelial cells play a key role in neovascular age-related macular degeneration (nAMD); however, the mechanisms underlying the angiogenic ability of these cells remain unclear. Herein, we investigated the effects of the senescent adult retinal pigment epithelial cell line-19 (ARPE-19) on wound healing, cell migration and survival, and tube formation abilities of human umbilical vein endothelial cells (HUVECs). Additionally, we used Brown Norway rats to establish a laser-induced choroidal neovascularization (CNV) model for further nAMD-related studies. We found that the wound healing, cell migration, and tube formation abilities of HUVECs were significantly enhanced following culture in conditioned media from senescent ARPE-19 cells; this was attributed to the activation of the transforming growth factor β-activated kinase 1 (TAK1)/p38 MAPK pathway. Consistently, we found that the TAK1 inhibitors 5Z-7-oxozeaenol and takinib reversed the effects of conditioned media from senescent ARPE-19 cells on the wound healing, migration, survival, and tube formation abilities of HUVECs. We further investigated the therapeutic effects of 5Z-7-oxozeaenol on the laser-induced CNV rat model. We found that TAK1 was activated in IB4+ areas in laser-induced CNV lesions; inhibiting the activity of TAK1 using 5Z-7-oxozeaenol significantly alleviated CNV lesion formation and fluorescein leakage in fundus fluorescein angiography and greatly improved a-waves, b-waves, and OP values, as recorded by electroretinography. Thus, senescent RPE cells may promote angiogenesis via the TAK1/p38 MAPK pathway. Further, inhibiting TAK1 expression alleviates pathological neovascularization and improves retinal function in a laser-induced CNV rat model, highlighting the therapeutic potential of this approach for treating nAMD.

Neovascularization; Senescence; TAK1; nAMD.