👤 Danilo Iannetta

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. Show less

To investigate whether W' in the extreme-intensity domain is smaller, yet linked to the W' predicted by the severe-intensity time series. Twelve recreationally active participants (four females) completed 1) three extreme-intensity and three severe-intensity constant-power output (PO) trials to establish the PO duration series and to obtain W' within their respective domains (W'EXT and W'SVR, respectively); 2) two decremental protocols from extreme-to-severe (EXT1→SVR3) and from severe-to-severe POs (SVR2→SVR3); 3) one extreme- and one severe-intensity constant-PO trial preceded by priming exercise (EXT1P and SVR2P, respectively); and 4) control extreme- and severe-intensity constant-PO trials. Peak values for oxygen uptake (V̇O2peak), blood lactate concentration ([La-]b-peak), and minute ventilation (V̇Epeak) were also analyzed. W'EXT was significantly smaller than W'SVR (P < 0.001). There was no difference in W' between the composite EXT1→SVR3 and SVR2→SVR3 and SVR3 alone (all P > 0.05). Priming-induced increase in W'EXT and W'SVR was not different (P = 0.401). V̇O2peak, V̇Epeak, and [La-]b-peak were all greater in EXT1P compared with EXT1 (all P < 0.05). We showed that W'EXT is smaller than W'SVR during cycling. Following task failure during EXT1, more work could be performed at SVR3 until complete depletion of W'SVR. Additionally, heavy-intensity priming exercise increased W'EXT and W'SVR by a similar magnitude. Collectively, these findings suggest that performance within the extreme-intensity domain is limited by mechanisms, at least in part, different from those that limit performance within the severe-intensity domain. Show less