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Receptor competition for ligand: Stochastic modelling and cellular fate

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The biology behind vascular signalling

The ability to grow vessels is crucial not only for the normal growth of tissue during development and wound-healing processes, but also for cancer maintenance. Given the emerging role of vessel growth processes (i.e., angiogenesis) in various diseases, we need to deepen our understanding of the molecular mechanisms that govern angiogenesis.

Fundamental Research
Health

In mammals, vascular endothelial cells line blood vessels and employ membrane-bound receptors such as the vascular endothelial growth factor (VEGF) receptor to function smoothly. VEGF receptor binds to VEGF for blood vessel development, new blood vessel sprouting and vascular repair. Imbalance in vascular system regulation has been linked to ocular and inflammatory disorders, ischaemic heart disease, neuro-degeneration, and other pathologies. Given the important role of the VEGF receptor-VEGF axis, scientists of the EU-funded VEGFR project wished to study the biology of the receptor and the mechanism behind this interaction. Towards this goal, they developed new stochastic mathematical models of VEGF receptor binding to its ligand, as well as receptor dimerisation, internalisation, signalling, trafficking, degradation, and subsequent regulation of endothelial cell fate. Researchers created stochastic versions of published deterministic models that take into consideration the biochemical species, their interaction relationships and the cellular compartments they can occupy. In addition, a computational platform for mathematical modelling and computer simulation of biochemical networks was used. The stochastic models proved sufficiently complex to describe the biochemical and cellular processes involved. However, the time-intensiveness of these models turned out to be an issue, as they required too much computing power in order to generate useful predictions. To circumvent this issue, scientists generated an experimental platform based on fluorescence imaging of living cells to study the dynamics of cell signalling upon stimulation of the VEGF receptor with VEGF. Cells were placed in an incubating chamber and a microfluidics device was employed to inoculate VEGF. Overall, important information was obtained regarding the dynamics of cell signalling upon stimulation with growth factors. The generated platform can be used to not only deepen our understanding of the molecular mechanisms of angiogenesis, but to also to study the biochemical changes induced by anti-angiogenesis drugs to combat cancer. Contrary to high expectations, these drugs have not produced the desirable results, necessitating further insight into their mechanism of action.

Keywords

Vascular system, cancer, VEGF, VEGFR, angiogenesis

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7 November 2020