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Bruna Caridi, Silvia Dragoni, Patric Turowski; The Role of Galectin-1 in Retinal Vascular Leakage. Invest. Ophthalmol. Vis. Sci. 2020;61(7):5160.
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Vascular endothelial growth factor (VEGF)-A induces pathological vascular dysfunction in many retinopathies and anti-VEGF treatments are widely used to stem associated vision-threatening complications. In diabetic macular oedema (DMO) vascular leakage only fully resolves for ca. 50 % of patients treated with anti-VEGFs, suggesting that other leakage pathways can drive oedema. Galectin-1 (Gal-1), a β-galactose-binding lectin, may also drive pathological vascular leakage during retinopathies. Importantly, aflibercept (AFL) binds Gal-1 and this may at least in part explain its reported superior clinical efficacy. The present study investigated the role of Gal-1 in the healthy and diseased retina, with focus on vascular leakage.
Gal-1 distribution was studied by immunohistochemistry in retinae from healthy mice (wild type and Gal-1-KO) or following induction of oxygen-induced retinopathy (OIR), as well as paraffin embedded retinae of post mortem (non-diabetic and diabetic) human eyes. Permeability changes in response to VEGF-A or Gal-1 were assessed in rat retinal explants and primary microvascular endothelial cells (MVECs) and further characterised using small molecule inhibitors and shRNA.
Based on publicly available single cell RNA data, Gal-1 expression is restricted to extravascular cells. We found that Gal-1 expression was very low in healthy retina, but strongly upregulated in disease, e.g. following OIR in rodents or diabetes in humans. Expression was not in endothelial cells but found adjacent to the vasculature, primarily in and around Muller Cells, and correlated well with extravasated IgG in diabetic human retina. Gal-1 induced permeability both in retinal microvessels ex vivo and in MVECs, but similar to that seen with VEGF-A only from the abluminal side. VEGFR2 and VEGFR1 were both required to mediate Gal-1-induced leakage. Furthermore, signaling mediating Gal-1-induced permeability involved Ca2+, eNOS, and p38 and thus overlapped with that of VEGF-A. AFL neutralised permeability induced by both VEGF-A and Gal-1.
Our data confirms a potential role of Gal-1 in the pathogenesis of retinopathies, in particular diabetic retinal vascular complications. Importantly, we find that Gal-1 affects endothelial cells by binding to VEGF receptors and mimicking VEGF-A function, thus also explaining how AFL may be effective towards as VEGF-A-independent but VEGF receptor-dependent process.
This is a 2020 ARVO Annual Meeting abstract.
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