The role of ADAMTS-4 and ADAMTS-1 in angiogenesis

Endothelial cells (ECs) form the innermost layer of all blood vessels, and their function and behaviour are important in angiogenesis. VEGF is the most potent angiogenic factor stimulating EC proliferation, migration, and differentiation as well as survival. Vascular endothelial growth factor receptor 2 (VEGFR2) is the major VEGF receptor which mediates VEGF-induced angiogenesis on ECs. Neuropilin 1 (NRPI) is a VEGF co-receptor that enhances VEGF-stimulated VEGFR2 angiogenic signals. A disintegrin and metalloproteinase with thrombospondin repeats (ADAMTS)-I, -2, -5, -8, and -9 have been shown to be anti-angiogenic. Our preliminary data suggested that ADAMTS-4 was expressed by two types of ECs, human umbilical vein endothelial cells (HUVECs) and human dennal microvascular endothelial cells (HuDMECs), and it inhibited endothelial cell differentiation so this thesis tested the hypothesis that ADAMTS-4 may be an anti-angiogenic molecule. For the first time, this thesis demonstrated that ADAMTS-I bound to NRPI by co-IP, and that ADAMTS-4 may also interact with NRPI. These potential bindings between ADAMTSs and NRP 1 may play roles in neuron system such as neuron development and axon guidance or in angiogenesis. These new interactions between ADAMTS-I, ADAMTS-4 and VEGF signalling complexes may point to new mechanisms of angiogenesis as NRPI has been reported to be more than just a VEGF co-receptor. Also, using co-IP an interaction between ADAMTS-4 and VEGF was demonstrated for the first time which may result in its effects on VEGF-mediated HuDMEC behaviour. Indeed, ADAMTS-4 reduced VEGF-stimulated VEGFR2 phosphorylation and also inhibited VEGF-induced HuDMEC differentiation and migration suggesting that ADAMTS-4 has anti-angiogenic activity. Sequence alignment of all 19 human ADAMTSs showed a high degree of similarity in the thrombospondin repeats suggesting that all 19 ADAMTSs could be anti-angiogenic.EThOS - Electronic Theses Online ServiceGBUnited Kingdo