Aspalter, IM; (2014) Molecular regulation of tip cell competition during sprouting angiogenesis. Doctoral thesis , UCL (University College London).

Abstract

Sprouting angiogenesis describes the formation of blood vessels from preexisting ones, a process guided by leading endothelial tip cells, followed by stalk cells. It has previously been established that the transient and dynamic specification of both phenotypes is mediated by DLL4/NOTCH signalling, which is primarily actuated by vascular endothelial growth factor (VEGF) and the corresponding vascular endothelial growth factor receptor 2 (VEGFR-2). The ability of a cell to outcompete its neighbour is determined by VEGFR signalling mediated production of DLL4 and subsequent activation of NOTCH in the adjacent cell. The stalk cell phenotype, induced by NOTCH activation, is reinforced by SMAD signalling through a crosstalk between both pathways. However, the downstream effectors of NOTCH and the molecular link to SMAD signalling in tip cell competition are unknown. During my PhD I have identified Neuropilin-1 (NRP1) as a critical NOTCHregulated determinant of tip/stalk specification. I have found that endothelial cells lacking one or both functional alleles of NRP1 are unable to form tip cells when competing with WT cells. Despite NRP1 having been previously described as a coreceptor of VEGFR-2, my data indicate that NRP1 functions independently of VEGFR-2 during tip/stalk selection. Furthermore, I have shown that inhibition of NOTCH is not sufficient to rescue the profound stalk cell phenotype of NRP1 deficient cells. Thus, I have identified NRP1 as the first bona fide downstream effector of NOTCH signalling in regulating angiogenesis. Furthermore, my data provides the missing link between NOTCH and SMAD signalling in stalk cell specification, as it shows NRP1 to be a negative regulator of the TGF- β/ALK5/SMAD2 pathway. Additionally, in contrast to NOTCH ablation, inhibition of ALK5 quantitatively restores the ability of NRP1 null cells to contribute to the tip position. I conclude that NRP1 is a key regulator of tip/stalk cell specification in sprouting angiogenesis; differential NRP1 levels act as key effector

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