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VEGF Isoforms and NRP1 in Vascular Hyperpermeability

Brash, James Thomas; (2018) VEGF Isoforms and NRP1 in Vascular Hyperpermeability. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The cardiovascular system serves to deliver oxygen and nutrients to the tissues of the body whilst simultaneously removing waste products. Blood vessels display a degree of basal permeability to achieve this function, which is regulated at the level of the endothelial monolayer. In response to certain stimuli, the integrity of the endothelial barrier is reduced, rendering blood vessels hyperpermeable. Best known as a potent inducer of angiogenesis, the vascular endothelial growth factor (VEGF) was originally identified as a vascular permeability factor. In certain diseases, such as those characterised by ischemia, VEGF upregulation causes vascular hyperpermeability and pathological oedema. VEGF exists in three major isoforms, termed VEGF120, VEGF164 and VEGF188, which variably engage one or more of several VEGF receptors, termed VEGFR1, VEGFR2 and NRP1. A better understanding of the how the different VEGF isoforms engage their receptors and downstream signalling pathways to promote vascular hyperpermeability may help refine current therapeutic strategies to target VEGF-induced oedema. In this volume of work, I have studied VEGF induced vascular hyperpermeability from several perspectives. Using an in vivo model of vascular hyperpermeability, I have compared VEGF isoform potency and investigated which receptors are required by different VEGF isoforms to promote vascular leakage. Using tissue culture models of vascular endothelium coupled with biochemical techniques, I have determined how VEGF isoforms and their receptors affect known hyperpermeability signal transduction pathways. Specifically, I have shown that NRP1 and its cytoplasmic domain (NCD) impact two VEGF hyperpermeability signalling axes, and that the NCD interacts with proteins previously linked to endothelial tight junctions and paracellular permeability. Finally, I have examined the expression of VEGF isoforms in several disease models that are characterised by vascular hyperpermeability.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: VEGF Isoforms and NRP1 in Vascular Hyperpermeability
Event: UCL (University College London)
Language: English
UCL classification: UCL
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/10058912
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