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Angiogenesis and vascular leakage in diabetic retinopathy

Laughlin, William Edward; (2018) Angiogenesis and vascular leakage in diabetic retinopathy. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and a leading cause of blindness. Increased vascular permeability in the retina following blood-retinal barrier (BRB) breakdown is a clinically significant event and a major cause of vision loss. VEGF blockade, despite being the only treatment to improve visual acuity, has a limited effectiveness for a majority of patients. A significant proportion of patients develop resistance to treatment, which implies that other factors are also involved in the pathology of this disease. There is currently a major unmet clinical need for therapeutics which target the early stages of DR prior to the onset of overt vascular symptoms. The aim of this thesis was to investigate early diabetes-induced changes to the retina and their effects on the vasculature, in order to identify novel potential therapeutic targets. This was achieved by investigating the effects of high glucose and glycated albumin on the vasculature using the mouse metatarsal assay, an ex vivo model of angiogenesis and the effects of diabetes on the retina with the streptozotocin-induced diabetic mouse. Both high glucose and glycated albumin altered angiogenesis in the metatarsal assay. Investigation of the diabetic mouse retina revealed evidence of increased inflammation and oxidative stress at the cellular and molecular level, accompanied with evidence of vascular leakage. qPCR analysis revealed an increase in Angptl6 and Lrg1 expression of which had not been investigated in the diabetic mouse retina before. Studies with transgenic mouse models implied that Lrg1 is involved in the early stages of pathophysiology of DR and may be a suitable therapeutic target prior to the onset of overt vascular symptoms.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Angiogenesis and vascular leakage in diabetic retinopathy
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10043874
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