Submacular tissue repair and fibrosis in neovascular macular degeneration: A predictable outcome secondary to a chronic age-related endotheliopathy

Fibrosis is strictly a histopathological term that refers to the replacement of functional tissue with permanent deposition of nonfunctional extracellular matrix (ECM), following an injury or disease, and can occur in any tissue in the body. In this histological setting, there is no overt difference between fibrosis and scarring. However, in the clinical context, fibrosis tends to be associated with chronic disease, as it ensures ongoing ECM deposition. This could be considered “excessive” when compared to ECM deposition in acute or end-stage chronic disease. This perspective highlights how fibrosis in neovascular age-related macular degeneration follows a stereotypical tissue repair process similar to that seen in other tissues and how salient biologic processes, such as aging and metabolic health, impact fibrosis development. In addition, we highlight the emerging and pivotal profibrogenic role played by progressive endothelial cell (EC) dysfunction, together with secondary blood flow impedance in the neovasculature. This results in abnormal vascular permeability, endothelial-to-mesenchymal transition, and EC senescence-associated secretory phenotype, processes that could potentially be targeted therapeutically. Finally, the dramatic impact of anti–vascular endothelial growth factor therapy, by primarily targeting permeability of the nascent microvasculature, on the natural history of fibrosis in neovascular age-related macular degeneration indirectly highlights the potentially significant role of ECs in fibrosis development and points toward how novel future targeting of these cells could further modulate the development of fibrosis.