Lange, CAK; (2012) Oxygen sensing mechanisms in retinal vascular development and disease. Doctoral thesis , UCL (University College London).

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Abstract

Oxygen sensing is a fundamental biological process which is critical for appropriate development of the eye and implicated in neovascular eye disease including age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity. This thesis describes a programme of work designed to investigate the role of hypoxia-inducible transcription factors (Hif’s), its downstream effector proteins, and its upstream regulator, the von Hippel Lindau protein (Vhl), in the development of the eye and neovascular eye disease. The first part of this work investigates the consequences of Hif activation in the developing retinal pigment epithelium (RPE) using a tissue specific knockout technology in mice. It demonstrates that appropriate regulation of Hif’s by Vhl is essential for normal RPE and iris development, ocular growth and vascular development and indicates that ocular hypoxia may be a previously unrecognised mechanism in the development of microphthalmia. The second part of this work studies the role of Hif1a in myeloid cells in the development of pathological neovascularisation using tissue-specific knockout technology and murine models for retinal and choroidal neovascularisation. It demonstrates that Hif1a signalling in myeloid cells contributes substantially to the development of retinal and choroidal neovascularisation and provides a rationale for developing antiangiogenic treatments that target Hif1a signalling in myeloid cells in neovascular eye disease. The third part of this work investigates the oxygen distribution in the vitreous and its relation to HIF1a and its downstream molecules in proliferative diabetic retinopathy (PDR) in man. It identifies significant intraocular oxygen gradients in PDR with areas of hyperoxia and hypoxia and demonstrates increased levels of HIF1a in the vitreous in PDR which correlate with increased levels of inflammatory and angiogenic cytokines in PDR. These findings suggest that HIF1a activation by inflammation and/or hypoxia is a central feature in the progression of PDR and that its inhibition may potentially serve as a target for therapeutic intervention.

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