Pathogenesis of neovascular age-related macular degeneration

Angiogenesis and CNV formation

Angiogenesis is the process of new vessel formation from preexisting ones. Under physiological and developmental conditions, angiogenesis is tightly regulated by a coordinated balance between pro- and antiangiogenic factors. Alterations in this fine-tuned balance could possibly lead to the increased production of proangiogenic mediators and the loss of inhibitory factors. For instance, neovascular AMD (nAMD) is characterized by the loss of this balance associated with choriocapillaris endothelial cell (CEC) dysfunction, leading to pathologic angiogenesis forming choroidal neovascularization (CNV). CNV breaks through Bruch’s membrane into the sub-RPE space and/or the subretinal space, leading to exudation, hemorrhage, retinal edema, pigment epithelial detachment, and fibrosis, which can cause severe irreversible vision loss. Within the last 15 years, anti-VEGF therapy has revolutionized the nAMD treatment paradigm. Intravitreal injection of VEGF inhibitors can prevent vision loss and even improve vision in patients with nAMD. But, nAMD still accounts for 90% of AMD-related vision loss. As CNV plays a central pathogenic role in nAMD, the underlying mechanisms of CNV formation need to be fully elucidated. Furthermore, a comprehensive approach targeting angiogenic control is required to improve outcomes of nAMD treatment. Because the function of several proangiogenic mediators is cross regulated, selecting an upstream and targeting multiple cascades are the promising strategies for nAMD therapy. This chapter emphasizes understanding key initiating factors for angiogenic signaling pathways and focuses on the mechanism of multiple cell–cell interaction in CEC migration and proliferation.