A systems biology perspective on sVEGFR1: its biological function, pathogenic role and therapeutic use

• Introduction ‐ Angiogenesis in physiology and pathology ‐ Angiogenesis in current medicine ‐ VEGF ligand and receptor system: where does sVEGFR1 fit? ‐ Ligands: the human VEGF family ‐ Membrane‐bound signalling receptors: VEGFRs ‐ Non‐signalling co‐receptors and matrix proteins: HSPGs and NRPs ‐ Soluble receptors: sVEGFR1, sVEGFR2, sNRP1 • Molecular biology of sVEGFR1 • Physiological and pathophysiological roles of sVEGFR1 • Molecular mechanism of sVEGFR1’s anti‐angiogenic potential • sVEGFR1 as a clinical marker for disease • Plasma VEGF and sVEGFR1: non‐uniform predictors of angiogenic status across all diseases • Systems biology perspective: unifying interpretation of plasma angiogenic markers ‐ Baseline heterogeneity in clinical measurements of healthy VEGF and sVEGFR1 levels in plasma ‐ Effect of sVEGFR1 on VEGF bioavailability: VEGF‐sVEGFR1 complexes ‐ Compartmental analysis: biotransport and biodistribution ‐ Pathogenic phenomenon versus compensatory response • Concluding remarks Angiogenesis is the growth of new capillaries from pre‐existent microvasculature. A wide range of pathological conditions, from atherosclerosis to cancer, can be attributed to either excessive or deficient angiogenesis. Central to the physiological regulation of angiogenesis is the vascular endothelial growth factor (VEGF) system – its ligands and receptors (VEGFRs) are thus prime molecular targets of pro‐angiogenic and anti‐angiogenic therapies. Of growing interest as a prognostic marker and therapeutic target in angiogenesis‐dependent diseases is soluble VEGF receptor‐1 (sVEGFR1, also known as sFlt‐1) – a truncated version of the cell membrane‐spanning VEGFR1. For instance, it is known that sVEGFR1 is involved in the endothelial dysfunction characterizing the pregnancy disorder of pre‐eclampsia, and sVEGFR1’s therapeutic potential as an anti‐angiogenic agent is being evaluated in pre‐clinical models of cancer. This mini review begins with an examination of the protein domain structure and biomolecular interactions of sVEGFR1 in relation to the full‐length VEGFR1. A synopsis of known and inferred physiological and pathological roles of sVEGFR1 is then given, with emphasis on the utility of computational systems biology models in deciphering the molecular mechanisms by which sVEGFR1’s purported biological functions occur. Finally, we present the need for a systems biology perspective in interpreting circulating VEGF and sVEGFR1 concentrations as surroga