Lampropoulou, Anastasia Syrmalenia; (2017) NRP1 regulation of endothelial cell signalling. Doctoral thesis , UCL (University College London).

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Abstract

Neuropilin 1 (NRP1) is a transmembrane protein that is essential for blood vessel growth and the regulation of vascular barrier properties. Yet, at the time of starting my PhD research, it was poorly understood how NRP1 affects endothelial cell behaviour to enhance either blood vessel growth or modulate vascular permeability. In particular, it was controversial whether NRP1 mainly acts to promote VEGF signalling through the VEGF receptor tyrosine kinase VEGFR2, or if it has other roles that synergise with VEGFR2 pathways to promote effective tissue vascularisation or vascular permeability. The aims of this study were therefore to (a) investigate whether NRP1 modulates angiogenesis and vascular hyperpermeability together with or independently of VEGFR2, (b) determine whether NRP1 regulates gene transcription to modulate endothelial behaviour; (c) define the molecular mechanism by which NRP1 regulates angiogenesis and VEGF-induced vascular hyperpermeability. My experiments have revealed that NRP1 promotes blood vessel growth both independently of, and synergistically with, VEGFR2-driven pathways. In particular, I found that VEGFR2-independent signalling involves the intracellular signal transducers CDC42 and ABL1 kinase, which promote actin remodelling during cell migration. Instead, my experiments have revealed that NRP1 promotes VEGF-induced vascular permeability in a complex with VEGFR2. Specifically, I found that that both NRP1 and VEGFR2 are required for the VEGF induced activation of SRC family kinases (SFKs), which are known to be essential for VEGF-induced vascular permeability signalling. Moreover, I found that NRP1 is important, because it is required for ABL1 activation, which in turn is essential for SFK activation in this pathway. Finally, I observed that NRP1 regulates several transcription factors and the expression of their target genes in endothelial cells, particularly genes involved in actin remodelling and cell proliferation. Together, this knowledge increases our understanding of the mechanisms of blood vessel formation and function. By identifying molecular pathways in blood vessel growth and permeability, these findings may, in the long run, benefit translational research aimed at developing novel therapies for diseases with vascular dysfunction.

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