Notch signaling in anti-VEGF resistant arteriolar choroidal neovascularization

Choroidal neovascularization (CNV) is a major pathological hallmark of fundus diseases, such as age-related macular degeneration, and is commonly treated with anti-vascular endothelial growth factor (VEGF) agents. However, resistance to or a suboptimal response to anti-VEGF therapy, particularly in arteriolar CNV, remains a significant clinical challenge. Arteriolar CNV, characterized by arterialized vessels, feeding arterioles with high blood flow, and prominent fibrosis, remains persistently active and responds poorly to standard anti-VEGF therapy. Notch signaling confers anti VEGF resistance in various diseases including cancer and corneal neovascularization. However, its role in anti-VEGF resistant arteriolar CNV has not been systematically summarized. This review highlights Notch signaling as a key regulator of both physiological and pathological arterial remodeling, driving arteriolar differentiation and contributing to resistance to VEGF inhibitors. In tumors, Notch signaling plays a crucial role in driving arteriolar neovessel formation, promoting macrophage-mediated vascular remodeling, and enhancing fibrosis, all of which contribute to anti-VEGF resistance. We also discuss whether and how similar mechanisms may operate in arteriolar CNV and proposes that Notch signaling represents a potential therapeutic target. Furthermore,combining Notch inhibitors with anti-VEGF therapy may improve outcomes in patients with arteriolar CNV resistant to anti-VEGF therapy, thereby providing a potential therapeutic strategies. Future studies are warranted to elucidate the specific roles of Notch signaling in CNV and optimize therapeutic strategies for improved safety and efficacy.