A Compartment Model of VEGF Distribution in Humans in the Presence of Soluble VEGF Receptor-1 Acting as a Ligand Trap
Figure 1
Schematic of Multi-Tissue Model of VEGF and sVEGFR1 Distributions.
A. Whole-body compartmentalization of solid tissues into ‘Calf’ vs. ‘Normal’ (rest of the body) compartments for a healthy subject. Characteristic geometries – parenchymal cell (grayish red), interstitial space (green/blue) and capillary space (endothelial cells (EC) in yellow, plasma in pink, red blood cells (RBC) in red) volume fractions; basement membrane (BM) thicknesses; and EC surface areas – were quantified from histological cross-sections of representative human skeletal muscles (gastrocnemius and vastus lateralis). Illustrations adapted from: ‘muscle man’ series from Andreas Vesalius, De Humani Corpis Fabrica, 1543, courtesy of the National Library of Medicine; histological micrographs from Baum et al. J Vasc Res 2007;44:202–213. Note: BM thicknesses and molecule sizes are not drawn to scale. B. Mass flows through 3-compartment model. VEGF and sVEGFR1 were secreted from parenchymal and endothelial cell sources respectively. Both were internalized upon binding with abluminal endothelial surface receptors. All soluble species were subjected to lymphatic drainage from interstitial space into the blood, bidirectional permeability through the endothelia, and direct clearance from the blood. C. Molecular Interactions between VEGF121 (yellow), VEGF165 (blue), sVEGFR1 (orange), interstitial matrix binding sites (glycosaminoglycans or “GAG”; purple), and the abluminal endothelial cell surface receptors VEGFR1 (red), VEGFR2 (blue), and NRP1 (green). The sVEGFR1 interactions modeled were: trapping of free VEGF121 (T1a) and VEGF165 (T2); giving NRP1s an indirect way of sequestering VEGF121 to the cell surface (T1b or T3); and displacing VEGF165 from interstitial matrix sites (D1b) through competitive binding (D1a). This model neglected sVEGFR1-heterodimerization with surface VEGFRs, thus ignoring the possible effect of sVEGFR1 in lowering the effective density of functional surface VEGFRs. Hence in this study, any effect that the presence of sVEGFR1 had on VEGF-signaling potential (i.e, the formation of VEGF-VEGFR complexes) resulted from sVEGFR1's influence on the effective concentration of interstitial free VEGF. D. Protein domains of full-length vs. soluble human VEGFR1. sVEGFR1's binding affinities for the VEGF ligand, interstitial matrix sites (e.g., heparan sulfate proteoglycans) and NRP1 were inferred from the identical first 6 immunoglobulin-like domains of the full-length VEGFR1.