The vascular endothelial growth factor (VEGF) family consists of critical cytokines that are implicated in controlling vascular survival and angiogenic sprouting. Recently VEGF inhibitors have been approved by the FDA to treat diseases of hypervascularization (cancer and macular degeneration), while increasing VEGF expression is a major research avenue for ischemic diseases such as peripheral artery disease and coronary artery disease, though clinical trials are as yet unsuccessful. VEGF is involved in at least 70 diseases as either cause or therapeutic target Regulation of VEGF signaling is therefore of critical importance for many therapeutic strategies. Recent evidence suggests that more VEGF is bound to the extracellular matrix in vivo than freely diffuses, and that these matrix-binding isoforms of VEGF control branching frequency and network density in vivo. The presentation of VEGF to the receptors by a matrix molecule may initiate a distinct signaling mode, but traditional in vitro cell culture models are unable to differentiate the soluble VEGF signal from the matrix-bound VEGF signal. In this proposal, we develop a combined experimentalcomputational approach to separate the soluble and matrix-bound VEGF signals. Using novel or available fibronectin mutants that do not bind VEGF (Aim 1), we will use state-of-the-art micropatteming techniques to plate endothelial cells on a substrate with gradients of VEGF binding ability (Aim 2). In vitro assays of proliferation, migration and survival will definitively show whether soluble VEGF or matrix-bound VEGF is the more potent stimulator of these critical endothelial cell decisions (Aim 2). We then propose to use in vivo transfection techniques to increase VEGF gradients and to block presentation of matrix-bound VEGF to receptor tyrosine kinases in vivo (Aim 3). This will test whether the in vitro endothelial cell culture is a good model of the decision-making of endothelial cells in vivo.
to public health: Inhibition or upregulation of yascular endpthelljaj groyvth factor (VEGF) is a therapeutic target in over 70 diseases as diverse as cahcelr, cororiafy artery disease and diabetic '?' retinopathy. The proposed research uses a novel combined computational and experimental method to elicit how VEGF initiates its signals and, if successful, will better define how to target it therapeutically.
|Clegg, Lindsay E; Mac Gabhann, Feilim (2018) A computational analysis of pro-angiogenic therapies for peripheral artery disease. Integr Biol (Camb) 10:18-33|
|Clegg, Lindsay E; Mac Gabhann, Feilim (2017) A computational analysis of in vivo VEGFR activation by multiple co-expressed ligands. PLoS Comput Biol 13:e1005445|
|Clegg, Lindsay E; Ganta, Vijay C; Annex, Brian H et al. (2017) Systems Pharmacology of VEGF165b in Peripheral Artery Disease. CPT Pharmacometrics Syst Pharmacol 6:833-844|
|Chappell, John C; Cluceru, Julia G; Nesmith, Jessica E et al. (2016) Flt-1 (VEGFR-1) coordinates discrete stages of blood vessel formation. Cardiovasc Res 111:84-93|
|Clegg, Lindsay Wendel; Mac Gabhann, Feilim (2015) Site-Specific Phosphorylation of VEGFR2 Is Mediated by Receptor Trafficking: Insights from a Computational Model. PLoS Comput Biol 11:e1004158|
|Clegg, Lindsay E; Mac Gabhann, Feilim (2015) Systems biology of the microvasculature. Integr Biol (Camb) 7:498-512|
|Clegg, Lindsay E; Mac Gabhann, Feilim (2015) Molecular mechanism matters: Benefits of mechanistic computational models for drug development. Pharmacol Res 99:149-54|
|Walpole, J; Chappell, J C; Cluceru, J G et al. (2015) Agent-based model of angiogenesis simulates capillary sprout initiation in multicellular networks. Integr Biol (Camb) 7:987-97|
|Vempati, Prakash; Popel, Aleksander S; Mac Gabhann, Feilim (2014) Extracellular regulation of VEGF: isoforms, proteolysis, and vascular patterning. Cytokine Growth Factor Rev 25:1-19|
|Logsdon, Elizabeth A; Finley, Stacey D; Popel, Aleksander S et al. (2014) A systems biology view of blood vessel growth and remodelling. J Cell Mol Med 18:1491-508|
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