VEGF and Neurotrophins Interaction in the Retinal Neurovascular Unit Homeostasis: A Target for Ocular Disease Treatment and Management.

Emerging evidence underscores the central role of the retinal neurovascular unit (RNVU) in the pathogenesis of major retinal disorders, including diabetic retinopathy, age-related macular degeneration, and glaucoma. Traditionally considered as primarily vascular diseases, these conditions are now increasingly recognized to involve early neurodegenerative processes that may precede vascular dysfunction. Although anti-VEGF therapies have revolutionized the treatment of neovascular retinal diseases, long-term VEGF inhibition has been associated with adverse effects, including retinal atrophy and diminished neuroprotection, underscoring the need for more targeted strategies. Recent studies have highlighted the differential roles of VEGF-A splice isoforms, particularly the pro-angiogenic VEGF-Axxxa and the anti-angiogenic VEGF-Axxxb, in maintaining RNVU homeostasis and contributing to disease progression. In parallel, neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have demonstrated the ability to exert neuroprotective, anti-inflammatory, and vasomodulatory effects, partly through modulation of VEGF-A signaling. Notably, we have recently demonstrated that NGF modulates VEGF-A isoform expression and VEGFR-2 levels in diabetic retinas, further supporting the hypothesis of a functional cross-talk between neurotrophins and angiogenic pathways. Based on this evidence, a new model is proposed, in which NGF and BDNF interact bidirectionally with VEGF-A to preserve RNVU integrity. This integrated therapeutic perspective, combining neurotrophic support with selective modulation of VEGF-A isoforms, may enhance treatment efficacy, reduce long-term side effects, and minimize the burden of care in chronic retinal neurodegenerative diseases.