Picking apart a fibronectin receptor network: How endothelial αvβ3-integrin, α5β1-integrin and neuropilin-1 regulate angiogenesis.

Taylor, James (2023) Picking apart a fibronectin receptor network: How endothelial αvβ3-integrin, α5β1-integrin and neuropilin-1 regulate angiogenesis. Doctoral thesis, University of East Anglia.

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Abstract

Angiogenesis, the growth of new blood vessels from pre-existing vessels, is crucial to both embryonic development and the maintenance of lifelong health, but also supports various pathological conditions. Its progression is complex, requiring the coordination of multiple signalling pathways and key regulators to deliver appropriate vascular expansion in response to proangiogenic stimuli. Some of its fundamental mechanisms have been characterised in great depth, revealing that angiogenesis relies heavily on the integrins αvβ3 and α5β1, as well as their principle extracellular matrix (ECM) ligand, fibronectin. Both integrins transmit signals bidirectionally between extracellular and intracellular compartments, sensing both ECM components and growth factor signals to regulate endothelial migration and proliferation. Therapeutic antagonism of these receptors was therefore assumed to provide anti-angiogenic benefit against pathological conditions where angiogenesis is dysregulated, namely solid tumours, where excessive vascular growth provides both nutrients and metastatic routes. Unfortunately, their mono-therapeutic blockade provided little clinical benefit and could even worsen prognosis by encouraging tumour vascularisation. Later findings attributed tumour angiogenic escape to endothelial VEGFR2 and neuropilin-1 (NRP1), one of a pair of pleiotropic co-receptors. NRP1 has since received great attention for its pairwise interactions with both αvβ3-integrin and α5β1-integrin. We believe these receptors operate within a complex trimeric network to orchestrate angiogenic processes, and that their intricate and off-time contradictory crosstalk is essential to our understanding of angiogenesis and the development of multi-target angiogenic therapies. To unpick this receptor network, we utilised genetically engineered mouse models in which our endothelial targets could be depleted either individually, or in combination, to study how they cooperate and compete to regulate developmental and pathological angiogenesis in vivo and in vitro. Our results indicate that whilst NRP1 plays a dominant role developmentally, integrin crosstalk regulates aspects of VEGFR2’s lifecycle.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Nicola Veasy
Date Deposited: 25 Jan 2024 10:54
Last Modified: 25 Jan 2024 10:54
URI: https://ueaeprints.uea.ac.uk/id/eprint/94254
DOI:

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