Researchers at the Babraham Institute have discovered a previously unknown signalling pathway that controls the formation and remodelling of blood vessels – a process called angiogenesis. The research, published this week in Science Signalling, reveals that a signalling protein called Arap3 is vital for establishing a circulatory system to nourish the developing embryo.
Mice lacking Arap3 die before birth because of the failure to ‘sprout’ new blood vessels during embryonic development, a process orchestrated by a family of proteins called phosphoinositide 3-kinases (PI3Ks) which regulate Arap3. While angiogenesis occurs during growth and development, it also serves to repair and rebuild blood vessels in adults after injury and in wound healing.
Understanding how these processes normally work therefore gives us a chance to work out what is happening when things go wrong. Angiogenesis also occurs in many pathological situations like cancer - tumours need a blood supply to obtain oxygen and nutrients. Age-related macular degeneration (AMD) is another condition involving aberrant growth of blood vessels, which causes irreversible loss of vision in the elderly.
The identification of a novel player in these pathways, and greater understanding of the mechanisms underpinning angiogenesis, therefore opens up the possibility of innovative drug targets for anti-angiogenic and pro-angiogenic therapies. ‘Cascades’ of signalling proteins communicate messages within a cell, or from one cell to its neighbours, to co-ordinate the development of an organism from an embryo. Arap3, which was discovered at Babraham, is an important signalling protein that regulates angiogenesis and is itself controlled by another signalling protein called phosphoinositide 3-kinase (PI3K). Arap3 in turn regulates two signalling proteins called RhoA and Arf6, which are important for cell motility, a crucial aspect of angiogenesis.
The lead author, Dr Sonja Vermeren explained, “We discovered that Arap3 is needed for angiogenesis when we studied a mouse lacking Arap3 and found that the embryos died because they didn’t form blood vessels correctly. Instead of an organised network of capillaries, the circulatory system of these embryos was highly disorganised. Remodelling of the primitive vascularisation had not progressed in an orderly fashion. The formation of new ‘sprouts’ during angiogenesis is a dynamic process that goes wrong when Arap3 is missing.”
PI3Ks are involved in a diverse range of activities inside cells, such as cell proliferation, motility and survival, which are central to angiogenesis. PI3Ks generate a lipid signalling molecule called phosphatidylinositol 3,4,5-trisphosphate, known as PIP3 for short, which localises to the inside of the outer cell membrane and activates PI3K effectors. About 50 PI3K effectors have been identified, which bind to and are regulated by PIP3. Arap3 is one such effector. Its unique binding specificity to and regulation by PIP3 may make it a suitable target for anti-angiogenic therapies.
The paper showed that ‘sprouting angiogenesis’ is particularly affected by loss of Arap3 and points to a previously unknown signalling pathway that controls developmental angiogenesis immediately downstream of the PI3K signalling protein, through Arap3 to Rho and Arf family small GTPases (key regulators of cellular events such as cell migration).
The Babraham Institute, an institute of the Biotechnology and Biological Sciences Research Council (BBSRC) where the research was conducted, is a centre for studying the basic biology of signalling inside and between cells, supporting BBSRC’s mission to drive advances in fundamental bioscience to underpin pharmceuticals and wellbeing. Results from these investigations, supported by both BBSRC and MRC (Medical Research Council), are contributing greater understanding to the processes through which angiogenesis occurs and may provide a rationale for the development of therapies to treat angiogenesis-based diseases.
Publication details: Gambardella L, Hemberger MC, Hughes B, Zudaire E, Andrews SR, Vermeren S (2010) PI3K signaling through the dual GTPase-activating protein ARAP3 is essential for developmental angiogenesis. Science Signaling 3 ra76 http://dx.doi.org/10.1126/scisignal.2001026
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About the Babraham Institute:
The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, through an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.
The Biotechnology and Biological Sciences Research Council (BBSRC) is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around £450 million in a wide range of research that makes a significant contribution to the quality of life for UK citizens and supports a number of important industrial stakeholders including the agriculture, food, chemical, health and well-being and pharmaceutical sectors. BBSRC carries out its mission by funding internationally competitive research, providing training in the biosciences, fostering opportunities for knowledge transfer and innovation and promoting interaction with the public and other stakeholders on issues of scientific interest in universities, centres and institutes.
28 October 2010