Description
Introduction
Pathological leakage and angiogenesis are hallmark features of diabetic retinopathy (DR), with vascular endothelial growth factor (VEGF) prominently driving disease. However, therapeutic targeting of VEGF is only fully effective for around half of patients, pointing to important yet unknown VEGF-independent mechanisms. Galectin-1, a β-galactoside-binding protein encoded by LGALS1, can activate VEGF receptors and sustain angiogenesis in anti-VEGF-resistant tumors.
Objectives
We aimed to investigate whether galectin-1 is a pathologically relevant leakage inducer in retinopathy, particularly in DR.
Methods
We combined immunostaining, proteomic, and single-cell transcriptomic analyses of human aqueous humour and retinal tissue to define the expression pattern of galectin-1/LGALS1. Rodent ex vivo retinal explants and cultured microvascular endothelial cells were used to measure vascular permeability in response to galectin-1 under various conditions. In vivo, the function of Lgals1 was interrogated in mice carrying knockouts, choroidal neovascularisation lesions, or rendered diabetic by streptozotocin intoxication.
Results
Galectin-1 levels were significantly higher in human aqueous humour from patients with DR compared to those with only diabetes. Immunostaining of retinal sections showed predominant localisation of galectin-1 to blood vessels, consistent with single-cell transcriptomic data showing the strongest expression in vascular and perivascular cells, especially in the context of retinovascular disease. Functionally, galectin-1 induced vascular leakage comparable to VEGF, using the same receptors and triggering similar downstream signalling. Under hypoxic conditions, the response of endothelial cells to galectin-1 was sensitized approximately 30-fold, an effect that could be attributed to differential surface glycosylation of endothelial cells. Validation of galectin-1 as a pathological inducer of retinal vascular leakage in vivo is underway.
Conclusion
Galectin-1 is upregulated in pathological conditions, enriched in the retinal neurovascular unit, and promotes vascular leakage, especially during hypoxia. These findings highlight galectin-1 as a potential therapeutic target in DR.
Lay Abstract
Good vision relies not just on light-sensing cells in the eye, but also on a network of tiny blood vessels that keep the retina nourished and healthy. When these vessels start leaking, they can cause serious sight-threatening diseases like diabetic eye disease and age-related macular degeneration, which affect hundreds of millions of people globally.
A protein called VEGF is known to drive this leakage, and medications that block it have helped many patients. However, up to half of patients don't improve with these treatments, meaning other culprits are likely involved.
Our research has identified another protein — Galectin-1 — that may play an important role. We found higher levels of Galectin-1 in people with these eye diseases compared to healthy individuals, and it appeared to cluster around blood vessels in the eye. In cells and animal studies, Galectin-1 caused blood vessels to leak in a similar way to VEGF. We are now investigating whether blocking Galectin-1 can prevent this damage in animal models of eye disease.
If successful, Galectin-1 could become a new treatment target that offers hope to many patients who don't respond to existing therapies.
| Lay Title | When VEGF is not the whole story behind vascular leakage in retinopathies |
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| Role | PhD Student |