Senescent retinal pigment epithelial cells, a type of cell in the eye, are known to be significantly involved in the development of neovascular age-related macular degeneration, often abbreviated as nAMD. However, the specific mechanisms that enable these senescent cells to promote the growth of new blood vessels are not yet fully understood.

In this study, we investigated how senescent adult retinal pigment epithelial cell line-19, or ARPE-19, cells affect various functions of human umbilical vein endothelial cells, or HUVECs. These functions included their ability to repair wounds, to migrate, to survive, and to form tube-like structures, which is a key step in the formation of new blood vessels. Additionally, we used Brown Norway rats to create a model of laser-induced choroidal neovascularization, or CNV, which mimics the abnormal blood vessel growth seen in nAMD, to further study this condition.

Our findings revealed that the wound healing, cell migration, and tube formation abilities of HUVECs were significantly increased when these cells were cultured in conditioned media, which is the growth medium that had previously been used to culture senescent ARPE-19 cells. We determined that this enhancement was due to the activation of a specific signaling pathway known as the transforming growth factor β-activated kinase 1, or TAK1, and p38 MAPK pathway.

Consistent with this, we found that the use of TAK1 inhibitors, specifically 5Z-7-oxozeaenol and takinib, was able to reverse the effects of the conditioned media from senescent ARPE-19 cells on the wound healing, migration, survival, and tube formation abilities of HUVECs. We further examined the potential therapeutic effects of 5Z-7-oxozeaenol in our laser-induced CNV rat model.

Our analysis showed that TAK1 was activated in areas positive for IB4, a marker for endothelial cells, within the CNV lesions induced by laser. Importantly, inhibiting the activity of TAK1 using 5Z-7-oxozeaenol significantly reduced the formation of CNV lesions and decreased the leakage of fluorescein, a marker of blood vessel permeability, as observed in fundus fluorescein angiography.

Furthermore, electroretinography, a test that measures the electrical activity of the retina, showed that inhibiting TAK1 greatly improved the a-waves, b-waves, and oscillatory potentials, indicating improved retinal function. Taken together, our results suggest that senescent retinal pigment epithelial cells may promote angiogenesis, the formation of new blood vessels, through the TAK1/p38 MAPK signaling pathway.

Moreover, inhibiting TAK1 expression appears to alleviate pathological neovascularization and improve retinal function in a rat model of laser-induced CNV, highlighting the potential of this approach as a therapy for treating neovascular age-related macular degeneration.