Regulation of VEGFR2 Activation in Skeletal Muscle by VEGF Isoforms with Differential ECM‐ and NRP1‐Binding: a Computational Study

Abstract

Tissues expressing only single isoforms of vascular endothelial growth factor (VEGF) form vascular networks that are structurally and functionally different. While the extracellular matrix (ECM)‐ and Neuropilin‐1 (NRP1)‐binding properties of the VEGF isoforms are known, the mechanism by which different isoforms lead to differential signaling downstream of VEGF receptor 2 (VEGFR2) is not well understood. Our objective is to extend a previously developed cell‐level model of VEGFR2 ligation, intracellular trafficking, and site‐specific phosphorylation to a whole‐body framework to study the implications of the ECM‐ and NRP1‐binding properties of VEGF isoforms in vivo. We include two VEGF receptors (VEGFR1 & VEGFR2), one coreceptor (NRP1), one soluble receptor (sVEGFR1), four isoforms of VEGF, and two isoforms of placental growth factor. We find that that distribution of VEGF isoforms in the body is controlled by the ECM‐binding properties of the ligands. We predict that the balance of NRP1‐binding and non‐NRP1‐binding isoforms alters the intracellular distribution of VEGFR2, and thus the relative activation on tyrosines 1175 and 1214, which control the cell behaviors of proliferation and migration/branching, respectively. We investigate changes in the predicted VEGFR2 activation pattern after application of pro‐angiogenic therapies including a VEGF isoform with very strong ECM‐binding. We show that the ECM‐ and NRP1‐ binding properties of VEGF and PlGF isoforms dictate their distribution in skeletal muscle, as well as their receptor‐binding and activating effects.Funding: DoD NDSEG Fellowship (LEC), NIH R01HL101200 (FMG), NIH R00HL093219 (FMG), Sloan Research Fellowship (FMG)