Systems biology of angiogenesis in ischemic diseases
Seminar Room 1, Newton Institute
Angiogenesis is the formation of new blood vessels from pre-existing microvasculature. Angiogenesis is important under physiological and pathological conditions (e.g., exercise, ischemic heart and peripheral vascular diseases). Over 70 diseases have been identified as angiogenesis dependent. Angiogenesis involves numerous processes such as: cell sensing of oxygen levels during hypoxia; upregulation of vascular endothelial growth factor (VEGF) by parenchymal and stromal cells, and of matrix metalloproteinases (MMPs) by endothelial cells; extracellular matrix (ECM) proteolysis and release of matrix-bound growth factors; endothelial cell migration, proliferation and differentiation; tubulogenesis or formation of capillary tubes; network morphogenesis; and vessel maturation and remodeling. We use computational approaches to explore the mechanisms and quantitative features of these processes. We use post-genomic bioinformatic approaches as an aid to model development. We have developed a series of molecular-level computational models that serve as modules in multiscale integrative models. These include a model of Hypoxia-Inducible Factor HIF1á regulation; models of interactions of several VEGF isoforms with their receptors VEGFR1, VEGFR2, co-receptor 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). In addition to these biochemically and biophysically detailed molecular-level models, we have developed a compartmental pharmacokinetic model that allows us to predict distribution of VEGF isoforms and intermediate products upon administration of pro-angiogenic factors, e.g. via gene delivery. The models will lead to a better understanding of therapeutic interventions in disease conditions including pro-angiogenic approaches to ischemic heart disease and peripheral vascular disease.