Angiogenesis is the growth of new microvessels from pre-existing vessels. It is important under physiological and pathological conditions (e.g., exercise, cancer, macular degeneration, rheumatoid arthritis, myocardial ischemia, peripheral arterial disease). Over 70 diseases have been identified as angiogenesis dependent. Angiogenesis involves numerous processes such as: cell sensing of oxygen during hypoxia; upregulation of vascular endothelial growth factor (VEGF), and of matrix metalloproteinases (MMPs); extracellular matrix (ECM) proteolysis and release of matrix-binding growth factors; endothelial cell migration, proliferation and differentiation; tubulogenesis or formation of capillary tubes; network morphogenesis or formation of capillary networks; and vessel maturation that involves recruitment of supporting cells such as pericytes and smooth muscle cells. We have developed several molecular-based computational models that will serve as modules in multi-scale integrative models. These include a model of Hypoxia-Inducible Factor HIF1, which is a transcription factor largely responsible for upregulation of VEGF in hypoxia; a model of interactions of VEGF splice isoforms with their receptors, such as VEGFR1, VEGFR2, Neuropilin-1 and heparan sulfate proteoglycans; and a model of ECM proteolysis by MMPs, specifically MMP2, MMP9 and membrane-type MT1-MMP, in the presence of tissue inhibitors of metalloproteinases (TIMPs). Databases of kinetic and physicochemical parameters are developed to accompany the models. We are developing a framework to incorporate these molecularly-detailed modules into a scheme that includes rule-based models, thus spanning the levels from molecular to microvascular.
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