A Compartment Model of VEGF Distribution in Humans in the Presence of Soluble VEGF Receptor-1 Acting as a Ligand Trap

Abstract

Vascular endothelial growth factor (VEGF), through its activation of cell surface receptor tyrosine kinases including VEGFR1 and VEGFR2, is a vital regulator of stimulatory and inhibitory processes that keep angiogenesis – new capillary growth from existing microvasculature – at a dynamic balance in normal physiology. Soluble VEGF receptor-1 (sVEGFR1) – a naturally-occurring truncated version of VEGFR1 lacking the transmembrane and intracellular signaling domains – has been postulated to exert inhibitory effects on angiogenic signaling via two mechanisms: direct sequestration of angiogenic ligands such as VEGF; or dominant-negative heterodimerization with surface VEGFRs. In pre-clinical studies, sVEGFR1 gene and protein therapy have demonstrated efficacy in inhibiting tumor angiogenesis; while in clinical studies, sVEGFR1 has shown utility as a diagnostic or prognostic marker in a widening array of angiogenesis–dependent diseases. Here we developed a novel computational multi-tissue model for recapitulating the dynamic systemic distributions of VEGF and sVEGFR1. Model features included: physiologically-based multi-scale compartmentalization of the human body; inter-compartmental macromolecular biotransport processes (vascular permeability, lymphatic drainage); and molecularly-detailed binding interactions between the ligand isoforms VEGF121 and VEGF165, signaling receptors VEGFR1 and VEGFR2, non-signaling co-receptor neuropilin-1 (NRP1), as well as sVEGFR1. The model was parameterized to represent a healthy human subject, whereupon we investigated the effects of sVEGFR1 on the distribution and activation of VEGF ligands and receptors. We assessed the healthy baseline stability of circulating VEGF and sVEGFR1 levels in plasma, as well as their reliability in indicating tissue-level angiogenic signaling potential. Unexpectedly, simulated results showed that sVEGFR1 – acting as a diffusible VEGF sink alone, i.e., without sVEGFR1-VEGFR heterodimerization – did not significantly lower interstitial VEGF, nor inhibit signaling potential in tissues. Additionally, the sensitivity of plasma VEGF and sVEGFR1 to physiological fluctuations in transport rates may partially account for the heterogeneity in clinical measurements of these circulating angiogenic markers, potentially hindering their diagnostic reliability for diseases.

Removal of Soluble Fms-Like Tyrosine Kinase-1 by Dextran Sulfate Apheresis in Preeclampsia

“…5,13,23,[35][36][37] In some women there appeared to be a rebound following apheresis (see Figures 2, 4, and 5). Given that the volume of distribution of sFlt-1 is large, with significant quantities bound to the interstitial matrix and ,20% of total body sFlt-1 circulating, 38 rebound following equilibration with the interstitial matrix compartment is not surprising. Although our ability to compare maternal changes in sFlt-1 levels over time in untreated contemporaneous preeclamptic controls to sFlt-1 levels in treated women should be considered exploratory, our study does emphasize, importantly, that any comparison of maternal and fetal outcomes between treated and untreated women should include women of similar preeclampsia severity.…”

Computational kinetic model of VEGF trapping by soluble VEGF receptor-1: effects of transendothelial and lymphatic macromolecular transport

“…1A). However, as quantified by these two metrics, antiangiogenic effects were not observed upon introduction of sVEGFR1 into our in silico model (40). In particular, increasing the intramuscular production of sVEGFR1 (i.e., the abluminal endothelial secretion rates of sVEGFR1) led to modest reductions in interstitial free VEGF levels and striking elevations in plasma free VEGF concentration (40).…”

“…Free sVEGFR1 was secreted abluminally from the endothelium into the interstitial fluid; luminal secretion of sVEGFR1 was neglected, for consistency with the model assumptions neglecting luminal insertion of surface VEGFRs (36,40). Once in the extracellular space, VEGF can be sequestered at interstitial matrix binding sites or form complexes with sVEGFR1 (sVEGFR1⅐…”

“…The soluble species-free VEGF (VEGF 121 and VEGF165), free sVEGFR1, and sVEGFR1 ⅐ VEGF complexes (sVEGFR1 ⅐ VEGF 121 and sVEGFR1 ⅐ VEGF165)-were subjected to three types of intercompartmental transport flows: 1) lymphatic drainage from the available interstitial fluid of muscle tissue compartments into the plasma of the blood compartment (40), which occurs unidirectionally in normal physiology (15) but can be obstructed in pathological conditions such as lymphedema (13); 2) bidirectional vascular permeability between the tissue interstitia and plasma (36); and 3) direct clearance out of the plasma via nonspecific elimination processes (e.g., kidney filtration and protein degradation) (36).…”

“…All model parameters are presented in the supplemental material: the control values for the VEGF and sVEGFR1 secretion rates, fitted to achieve the baseline concentrations of 1.5 pM of VEGF and 100 pM of sVEGFR1 in the plasma (40), are tabulated in Supplemental Table S5.…”