Description
Retinopathy of prematurity (ROP) is a leading cause of neonatal blindness, characterized by hyperoxia-induced vascular regression followed by pathological neovascularisation. Restoring physiological revascularisation while preventing aberrant neovascular tuft formation remains a major therapeutic challenge. Although anti-VEGF-A therapy is the current standard of care, frequent treatment failure and disease recurrence underscore the need for alternative strategies. Here, we investigate the endogenous role of class 3 semaphorins (SEMA3s) in pathological angiogenesis using genetically modified mouse models of oxygen-induced retinopathy (OIR) and physiological retinal angiogenesis. Inhibition of SEMA3 signalling enhanced retinal revascularisation and remodelled the neovascular niche in hypoxic retinas, shifting angiogenesis from pathological neovascularisation towards vascular repair. Loss of SEMA3E completely suppressed neovascular tuft formation and promoted reparative angiogenesis in hypoxic retinas. SEMA3E loss was associated with enhanced microglial activation and infiltration of the avascular zone in hypoxic retinas. These findings identify SEMA3E as a critical regulator of retinal vascular growth that operates independently of vascular endothelial growth factor (Vegfa) expression in hypoxic retinas. Inhibition of Sema3s led to increased vascular growth, not only under hypoxic conditions but also during development; Loss of SEMA3A, SEMA3E, or SEMA3F increased endothelial cell density during physiological angiogenesis. Mechanistically, SEMA3s crosstalk with VEGF signalling, with Vegfa upregulated during physiological angiogenesis. SEMA3s deficiency also regulated the formation of endothelial tight and adherent junctions. Targeting SEMA3 signalling may provide a novel therapeutic approach to promote reparative angiogenesis while limiting pathological neovascularisation in ROP and other ischaemic retinopathies.
Lay Abstract
Retinopathy of prematurity (ROP) is a serious condition and one of the leading causes of blindness in newborn babies. It happens when abnormal oxygen levels in early life damage the developing blood vessels in the retina. First, normal blood vessels can regress, and later, abnormal vessels can leak and damage vision.
A major challenge in treating ROP is finding ways to restore normal blood vessel growth while preventing abnormal blood vessels. Current treatments often target a molecule called VEGF-A, but these therapies do not always work well, and the disease can come back, highlighting the need for better approaches.
In this study, we investigate the natural role of class 3 Semaphorins (SEMA3s) in blood vessel growth in the retina. We use genetically modified mouse models that mimic both normal retinal development and the disease condition seen in ROP to understand how this molecule affects healthy and abnormal blood vessel formation.
Overall, our findings suggest that SEMA3s play a beneficial role in the retina by promoting the growth of healthy blood vessels while preventing the formation of abnormal vessels. This effect highlights SEMA3s as promising targets for future therapies aimed at restoring healthy blood vessels while reducing harmful ones.
| Lay Title | Restoring Healthy Blood Vessels to Prevent Childhood Blindness |
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| Role | PhD Student |