Limits...
A compartment model of VEGF distribution in humans in the presence of soluble VEGF receptor-1 acting as a ligand trap.

Wu FT, Stefanini MO, Mac Gabhann F, Popel AS - PLoS ONE (2009)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. florence.wu@jhu.edu

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 VEGF(121) and VEGF(165), 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.

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Basal Steady-State Flow Profiles of Free VEGF (left), sVEGFR1-VEGF Complexes (middle), Free sVEGFR1 (right).Solid-colored arrows represent intra-compartmental flows (i.e., secretion, internalization) and inter-compartmental flows (i.e., net vascular permeability, lymph flow, plasma clearance), with their relative magnitudes reflected by arrow widths. Color-graded arrows between columns indicate mass transfer flows between species (i.e., net association of free VEGF and free sVEGFR1 to form sVEGFR1-VEGF complexes, or net dissociation of the complex back into its constituents).
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pone-0005108-g004: Basal Steady-State Flow Profiles of Free VEGF (left), sVEGFR1-VEGF Complexes (middle), Free sVEGFR1 (right).Solid-colored arrows represent intra-compartmental flows (i.e., secretion, internalization) and inter-compartmental flows (i.e., net vascular permeability, lymph flow, plasma clearance), with their relative magnitudes reflected by arrow widths. Color-graded arrows between columns indicate mass transfer flows between species (i.e., net association of free VEGF and free sVEGFR1 to form sVEGFR1-VEGF complexes, or net dissociation of the complex back into its constituents).

Mentions: In healthy humans at rest, the interstitial free VEGF concentration has been measured in vastus lateralis microdialysates to be about 12–50 pg/mL [135], [136], which converts to 0.26–1.1 pM based on 46-kDa VEGF dimers. We thus targeted a range of 0.5–1.0 pM in the “normal body” and “healthy calf” interstitia (Table 9). The basal interstitial sVEGFR1 concentrations have not been reported in the literature. We thus estimated a target range for interstitial sVEGFR1 concentrations – by scaling the target range for interstitial VEGF concentrations to the VEGF∶sVEGFR1 protein weight measurements in tibialis anterior (TA) homogenates in normal mice [19] – at about 0.6–1.2 pM (Table 9). Limitations were noted in extrapolating from homogenate measurements that did not discriminate between interstitial and intracellular proteins. Thus in the case that plasma and interstitial concentrations could not be simultaneously modeled, we opted to fit targeted ranges for plasma concentrations in violation of the interstitial targets.


A compartment model of VEGF distribution in humans in the presence of soluble VEGF receptor-1 acting as a ligand trap.

Wu FT, Stefanini MO, Mac Gabhann F, Popel AS - PLoS ONE (2009)

Basal Steady-State Flow Profiles of Free VEGF (left), sVEGFR1-VEGF Complexes (middle), Free sVEGFR1 (right).Solid-colored arrows represent intra-compartmental flows (i.e., secretion, internalization) and inter-compartmental flows (i.e., net vascular permeability, lymph flow, plasma clearance), with their relative magnitudes reflected by arrow widths. Color-graded arrows between columns indicate mass transfer flows between species (i.e., net association of free VEGF and free sVEGFR1 to form sVEGFR1-VEGF complexes, or net dissociation of the complex back into its constituents).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2663039&req=5

pone-0005108-g004: Basal Steady-State Flow Profiles of Free VEGF (left), sVEGFR1-VEGF Complexes (middle), Free sVEGFR1 (right).Solid-colored arrows represent intra-compartmental flows (i.e., secretion, internalization) and inter-compartmental flows (i.e., net vascular permeability, lymph flow, plasma clearance), with their relative magnitudes reflected by arrow widths. Color-graded arrows between columns indicate mass transfer flows between species (i.e., net association of free VEGF and free sVEGFR1 to form sVEGFR1-VEGF complexes, or net dissociation of the complex back into its constituents).
Mentions: In healthy humans at rest, the interstitial free VEGF concentration has been measured in vastus lateralis microdialysates to be about 12–50 pg/mL [135], [136], which converts to 0.26–1.1 pM based on 46-kDa VEGF dimers. We thus targeted a range of 0.5–1.0 pM in the “normal body” and “healthy calf” interstitia (Table 9). The basal interstitial sVEGFR1 concentrations have not been reported in the literature. We thus estimated a target range for interstitial sVEGFR1 concentrations – by scaling the target range for interstitial VEGF concentrations to the VEGF∶sVEGFR1 protein weight measurements in tibialis anterior (TA) homogenates in normal mice [19] – at about 0.6–1.2 pM (Table 9). Limitations were noted in extrapolating from homogenate measurements that did not discriminate between interstitial and intracellular proteins. Thus in the case that plasma and interstitial concentrations could not be simultaneously modeled, we opted to fit targeted ranges for plasma concentrations in violation of the interstitial targets.

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. florence.wu@jhu.edu

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 VEGF(121) and VEGF(165), 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.

Show MeSH
Related in: MedlinePlus