New Roles for VEGFR1 in Angiogenesis

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SUMMARY The Vascular Endothelial Growth Factor (VEGF) family of ligands, and their receptor tyrosine kinase family, comprise the VEGF-VEGFR superfamily that plays a central role in the control of blood vessel growth (angiogenesis) in development, in adult physiology, and in over 70 diseases. VEGFs and VEGFRs are therefore key therapeutic targets across many high-mortality and high-morbidity illnesses. However, the results of attempts to treat diseases by targeting VEGFs and VEGFRs have been mixed. Some successes have been seen in angiogenesis inhibition for cancer and retinopathy; but in peripheral and coronary artery diseases, over a dozen human clinical trials delivering VEGF have failed to increase angiogenesis and perfusion, despite success in preclinical animal models. This inability to successfully bridge treatment from animals to humans shows that we do not sufficiently understand the multi-ligand, multi-receptor VEGF-VEGFR system. Only through a quantitative understanding of the complex system, using a framework under which we can compare mouse and human in a meaningful way, will we be able to successfully make predictions regarding treatment. Most receptor work to date has focused on just one of the three VEGFRs expressed by endothelial cells, VEGFR2, while VEGFR1, which is robustly expressed in most endothelial cells, has been relatively ignored. However, our recent studies have shown that the plasma membrane-resident form of VEGFR1 has two important roles in endothelial cell biology: it transduces signals itself via phosphoSTAT3, independent of VEGFR2 activation; and it sequesters ligand, withholding it from VEGFR2 and modulating VEGFR2 signaling. We term these the `signaling' role and the `decoy' role of VEGFR1. Both the ligand-sequestering decoy role and signaling role of membrane-bound (m)VEGFR1 likely contribute to angiogenesis. We hypothesize that the relative importance of signaling vs decoy depends on ligand and receptor expression, and on the regulation of receptor trafficking and stability. In this study, we will use an integrative approach to combine the expertise of our labs: computational modeling; mouse and human endothelial cell culture assays; and targeted therapeutic interventions in mice and humans. This integrated approach will enable us to isolate and quantify the signaling and decoy effects, and to define and refine their relative contributions to angiogenesis. The project goals are to: (1) build and validate the first computational model of mVEGFR1; (2) define and quantify the signaling and decoy roles of mVEGFR1; and (3) predict and test the effect of mVEGFR1's roles on therapies in vivo. Our central hypothesis is that a predictive computational framework that integrates mVEGFR1 ligand-binding, activation, trafficking, stability, and signaling will identify the modulations needed to achieve therapeutic angiogenesis. The outcome of this study will be a better understanding of mVEGFR1 biology and its impact on development and disease; our combined computational and experimental approach will elucidate the roles of mVEGFR1 more completely than computational or experimental approaches alone. !