Neuropilin-2 as a Novel Angiogenic Player: deciphering the contributions of neuropilin-2 during developmental and pathological angiogenesis

Benwell, Christopher (2022) Neuropilin-2 as a Novel Angiogenic Player: deciphering the contributions of neuropilin-2 during developmental and pathological angiogenesis. Doctoral thesis, University of East Anglia.

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Angiogenesis, the growth of neovasculature from pre-existing vessels, is driven by the stimulation of endothelial cells (ECs) by pro-angiogenic factors to invade the surrounding tissue and expand the vascular network. The extracellular matrix (ECM) component fibronectin (FN), and its canonical receptors, α5β1 and αvβ3 integrins are upregulated on angiogenic vasculature. Historically, the selective targeting of these FN receptors was postulated to provide directed anti-angiogenic therapy against pathologies typified by uncontrolled vascular growth such as cancer and retinopathy. Genetic ablation of these integrins however, proved not to inhibit the development of excessive vascularisation, and in some cases even accelerated the pathological phenotype. It is now believed that the failure of such integrin-based therapies can be attributed to the action of VEGF co-receptors, such as neuropilin-1 (NRP1) and neuropilin-2 (NRP2), to rescue and promote a pro-angiogenic phenotype. Unlike NRP1, far less is known about NRP2's role in microvascular ECs during angiogenesis, and therefore we sought to characterise NRP2's interaction with α5β1 integrin in ECs and investigate whether a dual contribution with NRP1 exists to promote developmental and pathological angiogenesis. To achieve this, we implemented siRNA-mediated depletion in vitro, and developed and employed genetically modified mouse models (GEMMs) in vivo to study the angiogenic consequences of inducing EC specific deletion of NRP2 alone, or in tandem with α5 integrin or NRP1. Our results indicate that NRP2 promotes polarised EC migration and adhesion to FN by directing the cellular trafficking of α5 integrin-phospho-focal adhesion kinase (p-FAK) complexes in a Rab11-dependent manner. By utilising both physiological and pathological models of angiogenesis, we also provide evidence that NRP2 promotes the formation of stable cell-matrix interactions to facilitate tip cell sprouting in the postnatal retina, and is essential for tumour vascularisation. In addition, by targeting both endothelial NRPs we were able to successfully arrest tumour angiogenesis completely.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Chris White
Date Deposited: 30 Jan 2023 10:45
Last Modified: 30 Jan 2023 10:45


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