ADP Pathway Uncovers Mechanism Behind Anti-VEGF Treatment Escape, Paving the Way for New Ophthalmic Drugs

Neovascular eye diseases are a major threat to vision in the elderly. While anti-VEGF drugs serve as the mainstream clinical treatment, some patients experience treatment failure and disease progression. A study published in PNAS has uncovered a key explanation for this clinical challenge, confirming that adenosine diphosphate (ADP) triggers a pro-angiogenic pathway independent of VEGF.

Research indicates that ADP specifically stimulates the proliferation of choroidal and retinal microvascular endothelial cells. By binding to the purinergic receptor P2Y1, ADP activates the MAPK signaling pathway and drives the formation of abnormal new blood vessels. Experiments have proven that conventional anti-VEGF agents cannot block this pathway, whereas P2Y1-targeted antagonists effectively inhibit cell proliferation. Animal experiments and single-cell transcriptomic analyses further validate this mechanism, confirming the specific expression of P2Y1 in human choroidal endothelial cells.

The ADP-P2Y1 signaling cascade revealed in this study elucidates the intrinsic mechanism of clinical treatment escape. The identification of this novel target not only advances the pathological research on ocular vascular disorders, but also opens new avenues for developing innovative ophthalmic targeted therapies and optimizing clinical regimens, holding great potential for clinical translation.

FOR DETAIL:  https://doi.org/10.1073/pnas.2418752122

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