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bioRxiv · 10.1101/2024.04.17.589627

Endothelial c-Src mediates neovascular tuft formation in Oxygen-Induced Retinopathy

Frampton, E.·Som, P.·Hill, B.·Yu, A.·Noordstra, I.·Gordon, E.·Schimmel, L.
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Abstract

IntroductionVascular retinopathy, characterised by abnormal blood vessel growth in the retina, frequently results in vision impairment or loss. Neovascular tufts, a distinctive pathological feature of this condition, are highly leaky blood vessel structures, exacerbating secondary complications. Despite their clinical significance, the mechanisms underlying tuft development are not fully elucidated, posing challenges for effective management and treatment of vascular retinopathy. In this study, we investigate the role of c-Src in neovascular tuft formation. Although c-Src has been acknowledged as a pivotal regulator in developmental angiogenesis within the retinal vasculature, its specific role in governing pathological retinal angiogenesis remains to be fully understood. MethodsWe utilised the Oxygen-Induced Retinopathy (OIR) model to induce the formation of neovascular tufts in both Cre-mediated vascular specific c-Src knockout mice and their wildtype littermates. Subsequently, we conducted high-resolution imaging and analysis of isolated retinas, to elucidate the precise role of c-Src in the formation of vascular tufts. Resultsc-Src depletion demonstrated a significant reduction in the formation of neovascular tufts within the OIR model, underscoring the pivotal role of c-Src in pathological retinal angiogenesis. Notably, this decrease in tuft formation was observed independently of any alterations in cell death, cell proliferation or cell adhesion and the absence of c-Src did not impact tuft pericyte coverage and junctional morphology. ConclusionThese findings underscore the critical role of c-Src in the pathogenesis of neovascular tufts in vascular retinopathy. Understanding the molecular mechanisms involving c-Src may offer valuable insights for the development of targeted therapies aimed at mitigating vision-threatening complications associated with retinopathy.

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Frampton, E., Som, P., Hill, B., Yu, A., Noordstra, I., Gordon, E., Schimmel, L.. 2024-04-20. Endothelial c-Src mediates neovascular tuft formation in Oxygen-Induced Retinopathy. https://doi.org/10.1101/2024.04.17.589627

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