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UBC Theses and Dissertations

Effects of VEGFR-2 signalling in post-natal hematopoiesis and vasculogenesis Larrivee, Bruno


Vascular endothelial growth factor (VEGF) and its receptors play an essential role in the formation and maintenance of the hematopoietic and vascular compartments. Activation of the kinase activity of the VEGF receptor-2 (VEGFR-2) is triggered by binding to VEGF, which affects endothelial cell proliferation, permeability, and migration. Accumulating evidence suggests that VEGFR-2 signalling may play an important role in post-natal hematopoiesis and vasculogenesis. One of the goals of this work was to study some of the biological effects triggered by VEGFR-2 in isolation, without the interference of other VEGF receptors in the contexts of post-natal hematopoiesis and vasculogenesis. By inducing expression of the full length VEGFR-2 or of a VEGFR-2 construct that can be selectively activated in fibroblasts or hematopoietic progenitors, we show that VEGFR-2 can induce activation of the Erkl/2 mitogen activated protein (MAP) kinase, p38 MAP kinase and Akt signalling pathways. Moreover, VEGFR-2 activation can elicit biological responses such as cell proliferation, migration and survival in vitro. Using a bone marrow transplantation model, we also show that VEGFR-2 activation promotes the expansion of myeloid cells in vivo, in part through the up-regulation of the hematopoietic cytokine Granulocyte/Macrophage- Colony Stimulating Factor (GM-CSF). In the second part of the thesis, we confirm the existence of early endothelial progenitors in mice. These cells originate from the bone marrow and can integrate in the vasculature of tumours, although at a low frequency. VEGF does not modulate the occurrence or mobilization of these progenitors. We also demonstrate that these cells originate from hematopoietic stem cells and that they arise by cell differentiation, and not through cell fusion. The work presented in this thesis, by elucidating some of the effects triggered by VEGF signalling though VEGFR-2 in hematopoietic cells, could potentially lead to the development of therapies targeting the growth of malignant hematopoietic cells.

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