Abstract
Blood vessels play a role in virtually every medical condition. They transport white blood cells to sites of infection and inflammation; they can become blocked leading to heart attacks and strokes and can cause cancers to progress by feeding the tumour with nutrients and oxygen. Angiogenesis is a term used to describe the growth of new blood vessels. In the adult, angiogenesis is a critical process for wound healing, menstruation and allowing the placenta to meet the nutritional demands of a growing baby. However, when angiogenesis is not properly controlled, there can be serious health implications. In some conditions, there are not enough healthy blood vessels to provide the necessary oxygen and nutrients to the tissue, this can present as the pain in angina or intermittent claudication, conditions, which if left untreated can result in a heart attack or amputation of the lower limbs. On the other hand, in diseases such as cancer and age-related macular degeneration (AMD), the growth of new blood vessels is unwanted, as it leads to the spread of the tumour or blindness. So, therapies aimed at either promoting or reducing angiogenesis have the potential to make a huge impact in medicine. Unfortunately, it has not been easy to control blood vessel growth, which is thought to be because the factors that coordinate it are much more complicated than initially thought. One of the most important proteins involved in blood vessel growth is called Vascular Endothelial Growth Factor (VEGF). This protein binds to receptors on the surface of cells that only it can bind to, similar to a key only fitting a specific lock. Once this occurs proteins inside the cell are activated and cause the cells to divide, move around and form new vessels. The system becomes complicated because there are a number of different receptors that can come together in different ways and many different proteins inside the cell. The cell will respond in different ways and different proteins inside the cell will become active depending on which receptor or combination of receptors VEGF binds to. It is also thought that in particular diseases the combination and location of these receptors will be changed compared to normal tissues and this may contribute to the diseases. This research, being undertaken by a number of groups at the University of Edinburgh, aims to screen healthy and abnormal human tissues for a certain receptor combination that we think may be changed in some disorders, work out what controls the receptor combinations and if the proteins activated inside the cell are altered when VEGF binds to different receptor combinations. We will then use techniques to examine how the various combinations of VEGF receptors control angiogenesis in normal and abnormal conditions. Ultimately, we will use all the information we gain from this research to help produce more precise therapies to cause or prevent angiogenesis depending on the medical conditions being targeted.
Technical Summary
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 ischemic disease and reducing angiogenesis in cancers, would have tremendous clinical impact. Vascular endothelial growth factor (VEGF), its receptors, VEGFR-1 and VEGFR-2 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 demonstrated, but poorly studied. To investigate the function of the heterodimer between VEGFR-1 and VEGFR-2 (VEGFR1-2), I have generated a novel VEGFR1-2-specific ligand. Using this ligand I 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 will have a significant impact on the field. I am in a unique position to systematically characterise and explore the role of VEGFR1-2 in physiology and pathology and to ascertain its potential as a therapeutic avenue.
Planned Impact
The results from this study have translational potential, which will impact on improving diagnosis and treatment of disorders involving dysregulated angiogenesis, e.g. preeclampsia, cancer and ischaemic diseases. Within this five-year timeframe we will have a detailed understanding of the role of VEGFR heterodimerisation in normal physiology and under pathological conditions. We will understand how heterodimerisation is regulated by VEGF itself, and signalling feedback mechanisms. This work will be a critical addition to our knowledge of the VEGF receptor tyrosine kinase system and will hopefully, help to explain why targeting the VEGF system therapeutically is so difficult and alleviate these problems, allowing for more effective therapies to be introduced. These results will have academic beneficiaries within the University itself, enhanced by my cross College and Centre collaborations. Namely, collaboration between scientists and clinicians from the University/BHF Centre for Cardiovascular Science, the MRC Centre for Reproductive Health, the Tommy's Centre, the Centre for Regenerative Medicine and the Edinburgh CRUK Centre and the College of Science and Engineering. Centre, Institute and University impact will be realised by peer-viewed publications and grant funding applications, to expand this work and thus, boost the reputation of the University in this research field. By providing a bridge between cardiovascular science and cancer research, my findings are likely to have real impact in meeting unmet medical need in the area of pro- and anti-angiogenic therapy. With the expansion of this work, Dr Weich may commercialise the ligand via his biotech company, Reliatech. A readily available supply of the ligand marketed via Reliatech would allow research groups from around the world to undertake studies of this nature, accelerating discoveries and clinical applications. Findings with clinical relevance may lead to commercial value, which would allow investment back into this research. The knowledge achieved throughout my fellowship studies will hasten the development of methods and tools to target VEGFR heterodimerisation therapeutically and more broadly to determine how fine regulatory mechanisms of other systems involved in angiogenesis can be manipulated for greater clinical benefit, which has the potential to positively impact on society and wellbeing.
