Caridi, Bruna; (2022) The Role of Galectin-1 in Retinal Vascular Leakage. Doctoral thesis (Ph.D), UCL (University College London).

Abstract

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. Aflibercept (AFL) has shown greater clinical efficacy than other anti-VEGF agents currently available. AFL is a pharmacologically engineered glycoprotein, broadly based on domains of VEGF receptors. AFL binds Galectin-1 (Gal-1), a protein not related to the VEGF family, 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. In this study, I found that Gal-1 expression was low in the healthy retina, but strongly upregulated in disease. Expression was not in endothelial cells (ECs) but found adjacent to the vasculature, primarily in and around Müller Cells (MCs). Gal-1 induced permeability both in retinal microvessels explants and in microvascular ECs (MVEC). VEGF receptor 2 (VEGFR2) and VEGFR1 were both required to mediate Gal-1-induced leakage. Furthermore, signalling to mediate 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 confirmed the potential role of Gal-1 in the pathogenesis of retinopathies. Importantly, I found that Gal-1 mimicked VEGF-A by binding to VEGF receptors and to VEGF receptor-derived AFL, thus potentially explaining AFL's greater clinical effectiveness.

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