Compartment model of VEGF transport in blood and tissues. A, Schematic of a tissue cross section. VEGF165 can bind to glycosaminoglycan chains (GAG) and be sequestered in the extracellular matrix whereas VEGF121 cannot. The isoforms have different cell surface receptor binding profiles. B, Compartment model set-up. Three compartments are used in our simulations: blood, healthy and diseased tissues. The diseased tissue compartment is not used in all simulations. VEGF is secreted by parenchymal cells in the healthy and diseased compartments (q). VEGF transport between the blood and the tissue compartments is via transcapillary permeability (k
). VEGF receptors are expressed on the abluminal side of the endothelial cells and VEGF binding to these receptors can lead to internalization (k
). Plasma clearance for VEGF is present in the blood compartment (c
). C, Interactions between VEGF, cell surface receptors, extracellular matrix and basement membranes. VEGF121 binds to VEGFR2 but does not bind to NRP1. VEGF165 interacts with VEGFR2 or NRP1. Once bound, it can form a ternary complex VEGFR2- VEGF165- NRP1. VEGF165 can be sequestered by the ECM, PBM or EBM by binding to GAG chains. VEGF121 binds to VEGFR1. This receptor couples with NRP1 to form VEGFR1-NRP1 complex or the ternary complex VEGF121-VEGFR1-NRP1 if previously occupied by VEGF121. VEGF165 also binds to VEGFR1 but not to the VEGFR1-NRP1 complex. The receptors (VEGFR1, VEGFR2 and NRP1) are inserted or internalized at the cell surface.