Edinburgh Research Explorer

Dr Melissa Cudmore

MRC Career Development Fellow, Research Fellow

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Willingness to take PhD students: Yes

My research in a nutshell

Aberrant angiogenesis occurs in numerous pathologies, as a direct cause of disease, as well as contributing to condition severity and clinical outcome. Therapies aimed at promoting angiogenesis to tackle ischaemic disease and reducing angiogenesis in cancers, would have tremendous clinical impact. Vascular endothelial growth factor (VEGF), its tyrosine kinase receptors, VEGFR-1 and VEGFR-2, in homodimer form, are essential for developmental vasculogenesis and angiogenesis, physiological and pathological adult angiogenesis and endothelial homeostasis, but targeting this system for therapeutic angiogenesis has had limited success. Anti-VEGF antibodies and specific receptor inhibitors have proved to be disappointing therapeutically. However, the VEGF system is fundamental for blood vessel genesis, as such is unlikely to be the wrong target, it is paucity in the knowledge of the fine regulation of the VEGF system and feedback mechanisms necessary to inform, when, where and how to deliver the appropriate therapy to target this system effectively. Receptor heterodimerisation is a mechanism used to precisely regulate cell signal and function. Heterodimerisation of VEGF receptors has been widely shown to occur in any cell that co-expresses both receptors, and functional independence of the VEGF heterodimers from VEGF receptor homodimers has been demonstrated, however, much further work is necessary to determine the exact role of VEGF receptor heterodimerisation during vascular development. To investigate the function of the heterodimer between VEGFR-1 and VEGFR-2 (VEGFR1-2), we have generated a novel VEGFR1-2-specific ligand. Using this ligand we have shown that the heterodimer receptor mediates responses previously thought to be via VEGFR-1 homodimers and that VEGFR1-2 can negatively regulate VEGFR-2-mediated functions. Thus, it appears that VEGFR-1 subunits regulate VEGF activity predominantly by forming heterodimer receptors with VEGFR-2 subunits. This is a paradigm shift in the current thinking on the mechanism of action of VEGFR-1 and VEGFR-2 and our work is helping to elucidate the detailed molecular mechansims of VEGF function in physiology and patology.

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