Angiopoietin-2 signaling in retinal and choroidal vascular diseases: mechanisms, clinical evidence, and therapeutic implications

Abstract Currently, intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs remains the first-line therapy for most pathological retinal and choroidal vascular diseases. However, the suboptimal efficacy of conventional anti-VEGF drugs and the burden of repeated injections compromise treatment outcomes in retinal and choroidal vascular diseases, resulting in limited clinical benefit for patients and a higher likelihood of treatment discontinuation—highlighting a significant unmet medical need in current clinical practice. In pivotal randomized trials, next-generation anti-VEGF drugs—including faricimab, brolucizumab, and high-dose aflibercept—have demonstrated visual outcomes non-inferior to conventional anti-VEGF therapy, with additional anatomical improvements and extended treatment intervals in selected patients. Unlike conventional anti-VEGF drugs mainly targeting VEGF-A, faricimab simultaneously targets angiopoietin-2 (Ang-2) and VEGF-A, making Ang-2 a focus of attention. In this review, we investigate (1) the involvement of Ang-2, its counterparts and their intricate interplays in the pathological processes; (2) the biology and context-dependent signaling of Ang-2 and its counterparts; and (3) the potential contribution of Ang-2 and its counterparts in the pathological retinal/choroidal vascular diseases. This review will provide readers with a comprehensive understanding of the roles and mechanisms of Ang-2 in retinal/choroidal vascular diseases, which provides a foundation for the development of novel pharmacological agents targeting these diseases and also highlights the growing trend toward molecularly targeted and individualized therapies.