Plein, AR; (2015) Defining Novel Mechanisms in Cardiovascular Development. Doctoral thesis , UCL (University College London).

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Abstract

The cardiovasculature is one of the earliest organ systems to develop in the mammalian embryo and its formation relies on the transmembrane receptor neuropilin (NRP) 1. Thus, the cardiovasculature in NRP1 knockout mice develops abnormally. In addition, the cardiac outflow tract (OFT), a transient, embryonic vessel located at the arterial pole of the heart, fails to septate in these mutants. NRP1 has traditionally been thought to regulate these processes by binding to the vascular endothelial growth factor (VEGF) A in the vascular endothelium. Nevertheless, NRP1 is also expressed by non-endothelial cells and binds alternative ligands of the class 3 semaphorin (SEMA3) family. During my PhD, I contributed to two studies examining NRP1’s role in organ vascularisation, which revealed that non-endothelial NRP1 is dispensable for vascular development, and that NRP1 does not exclusively function as a VEGF-A receptor during this process. I also demonstrated that NRP1, instead of being required as a VEGF-A receptor during OFT remodelling, acts as a SEMA3C receptor to induce an endothelial-to-mesenchymal transition that enables OFT remodelling. In a complementary project, I investigated the role of vascular precursors marked by a novel lineage trace. Vascular progenitors contribute to the formation of the earliest embryonic vessels, but their involvement in later developmental and pathological vessel growth is less well understood. Using a Csf1r-Cre transgene, originally thought to be specific for the monocyte/macrophage lineage, I found that this transgene also labels a subpopulation of endothelial cells in brain and retinal vessels. This labelling was not caused by endothelial CSF1R or unspecific Csf1r-Cre or RosaYfp expression. Furthermore, by analysing embryos from myeloid/macrophage-deficient mice, I demonstrated that Csf1r-Cre-labelled endothelial cells were not derived from the myeloid/macrophage lineage. In adults, the analysis of bone marrow and blood from these mice as well as tamoxifen-inducible Csf1r-Cre mice suggested that Csf1r-Cre labels a bone marrow-derived population of cells that contributes to tissue-resident and circulating vascular precursors.

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