The apelin/APJ signaling axis in ocular neurovascular disorders: Molecular mechanisms and therapeutic strategies for angiogenesis and neurodegeneration

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The apelin/APJ system, a vital signal axis, regulates key physiological processes in multiple systems, including vascular permeability, inflammatory response and angiogenesis. However, in the pathophysiology of ocular neurovascular disorders, this signaling pathway exhibits dual functions that are highly dependent on the disease stage and microenvironment. Growing evidence suggests that during early disease stages, upregulation of the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway and downregulation of the NF-κB signaling cascade enable the system to exert vascular protection and neuroprotective effects. Conversely, in the late stages, stimulation by chronic hypoxia and ischemia strongly promotes pathological angiogenesis through the activation of the PI3K-Akt-mTORC1 and Ras-Raf-MEK-ERK cascades. Therefore, resolving this paradoxical behavior is essential for its clinical translation. Therefore, this review critically evaluates the stage-dependent dual roles of the apelin/APJ system in ocular neurovascular disorders. By utilizing ophthalmic diseases as highly representative and accessible models for the central nervous system, we dissect the molecular shift from vascular stability to pathological angiogenesis. Ultimately, as a disease stage biomarker and a novel therapeutic target for combating both systemic angiogenesis and neurodegeneration, we emphasize the translational potential of the apelin/APJ system.