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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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Steady-State and Dynamic Effects of Lymphatic Drainage Rates (kL).Steady-state effects of kL on VEGF and sVEGFR1 concentrations (A) and flows (B). Of the three transport parameters (kP, kL, kCL), increasing kL over two orders of magnitude about the control value resulted in the greatest fluctuations in steady-state concentrations: most significantly elevating plasma VEGF and sVEGFR1, while lowering interstitial sVEGFR1. Exceptions were noted with localized changes in kL – e.g., with increasing only kL,Normal from ‘CP’ to ‘PE’, the enhanced flushing of sVEGFR1 from the local interstitium into the plasma eventually spilled over through increased sVEGFR1 extravasation into the opposite compartment to elevate interstitial sVEGFR1 concentration there. In addition, a reversal in permeability flow of sVEGFR1-VEGF complex (red box) was noted for kL above control. ‘Lo’ = low; ‘Nite’ = night; ‘+’ = supine awake (control); ‘SE’ = whole-body steady exercise; ‘CP’ = calf-only peak exercise; ‘PE’ = whole-body peak exercise; ‘Hi’ = high. Dynamic Effects of kL on VEGF, sVEGFR1, and sR1-VEGF Concentrations (C). kL-driven fluctuations in VEGF and sVEGFR1 attained within physiological diurnal cycles were less than those attained during steady-state analyses but still were of very wide ranges. “Bed-rest days” (purple columns) consisted of 15 hrs of wakefulness limited to supine or sitting postures, followed by 9 hrs of sleep. “Active days” (yellow columns) consisted of 15-hrs of activity starting off with a peak in kL during early exercise and settling down to a steady running/walking rate, followed by 9 hrs of sleep. Reversed permeability flow of sVEGFR1-VEGF complex (red cross-hatching) was observed in the latter active waking hours. “Calf-limited activity days” (aqua column) are same as “bed-rest days” except that active kL was induced in the calf during the first 15 hrs of wakefulness. Stick-figure illustrations adapted from Olszewski et al. Lymphology 1977, 10(3):178–183.
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pone-0005108-g009: Steady-State and Dynamic Effects of Lymphatic Drainage Rates (kL).Steady-state effects of kL on VEGF and sVEGFR1 concentrations (A) and flows (B). Of the three transport parameters (kP, kL, kCL), increasing kL over two orders of magnitude about the control value resulted in the greatest fluctuations in steady-state concentrations: most significantly elevating plasma VEGF and sVEGFR1, while lowering interstitial sVEGFR1. Exceptions were noted with localized changes in kL – e.g., with increasing only kL,Normal from ‘CP’ to ‘PE’, the enhanced flushing of sVEGFR1 from the local interstitium into the plasma eventually spilled over through increased sVEGFR1 extravasation into the opposite compartment to elevate interstitial sVEGFR1 concentration there. In addition, a reversal in permeability flow of sVEGFR1-VEGF complex (red box) was noted for kL above control. ‘Lo’ = low; ‘Nite’ = night; ‘+’ = supine awake (control); ‘SE’ = whole-body steady exercise; ‘CP’ = calf-only peak exercise; ‘PE’ = whole-body peak exercise; ‘Hi’ = high. Dynamic Effects of kL on VEGF, sVEGFR1, and sR1-VEGF Concentrations (C). kL-driven fluctuations in VEGF and sVEGFR1 attained within physiological diurnal cycles were less than those attained during steady-state analyses but still were of very wide ranges. “Bed-rest days” (purple columns) consisted of 15 hrs of wakefulness limited to supine or sitting postures, followed by 9 hrs of sleep. “Active days” (yellow columns) consisted of 15-hrs of activity starting off with a peak in kL during early exercise and settling down to a steady running/walking rate, followed by 9 hrs of sleep. Reversed permeability flow of sVEGFR1-VEGF complex (red cross-hatching) was observed in the latter active waking hours. “Calf-limited activity days” (aqua column) are same as “bed-rest days” except that active kL was induced in the calf during the first 15 hrs of wakefulness. Stick-figure illustrations adapted from Olszewski et al. Lymphology 1977, 10(3):178–183.

Mentions: Transport parameters were independently varied over two orders of magnitude about control for sensitivity analysis. In plasma, steady-state concentrations of all soluble species were strongly dependent on transport rates, whereas in the interstitium, sVEGFR1 concentration was much more sensitive than VEGF to transport parameters. In general: increasing kP reduced plasma vs. interstitium gradients (i.e., closer to 1∶1) for both VEGF and sVEGFR1 concentrations (Fig. 8A); increasing kL lessened VEGF gradients but steepened sVEGFR1 gradients (Fig. 9A); while decreasing kCL reduced VEGF gradients without much effect on sVEGFR1 gradients (Fig. 10). Additionally, the current model showed that physiological fluctuations in transport parameters were ineffective in altering endothelial VEGFR occupancy, given their minute effect on interstitial free VEGF levels.


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)

Steady-State and Dynamic Effects of Lymphatic Drainage Rates (kL).Steady-state effects of kL on VEGF and sVEGFR1 concentrations (A) and flows (B). Of the three transport parameters (kP, kL, kCL), increasing kL over two orders of magnitude about the control value resulted in the greatest fluctuations in steady-state concentrations: most significantly elevating plasma VEGF and sVEGFR1, while lowering interstitial sVEGFR1. Exceptions were noted with localized changes in kL – e.g., with increasing only kL,Normal from ‘CP’ to ‘PE’, the enhanced flushing of sVEGFR1 from the local interstitium into the plasma eventually spilled over through increased sVEGFR1 extravasation into the opposite compartment to elevate interstitial sVEGFR1 concentration there. In addition, a reversal in permeability flow of sVEGFR1-VEGF complex (red box) was noted for kL above control. ‘Lo’ = low; ‘Nite’ = night; ‘+’ = supine awake (control); ‘SE’ = whole-body steady exercise; ‘CP’ = calf-only peak exercise; ‘PE’ = whole-body peak exercise; ‘Hi’ = high. Dynamic Effects of kL on VEGF, sVEGFR1, and sR1-VEGF Concentrations (C). kL-driven fluctuations in VEGF and sVEGFR1 attained within physiological diurnal cycles were less than those attained during steady-state analyses but still were of very wide ranges. “Bed-rest days” (purple columns) consisted of 15 hrs of wakefulness limited to supine or sitting postures, followed by 9 hrs of sleep. “Active days” (yellow columns) consisted of 15-hrs of activity starting off with a peak in kL during early exercise and settling down to a steady running/walking rate, followed by 9 hrs of sleep. Reversed permeability flow of sVEGFR1-VEGF complex (red cross-hatching) was observed in the latter active waking hours. “Calf-limited activity days” (aqua column) are same as “bed-rest days” except that active kL was induced in the calf during the first 15 hrs of wakefulness. Stick-figure illustrations adapted from Olszewski et al. Lymphology 1977, 10(3):178–183.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2663039&req=5

pone-0005108-g009: Steady-State and Dynamic Effects of Lymphatic Drainage Rates (kL).Steady-state effects of kL on VEGF and sVEGFR1 concentrations (A) and flows (B). Of the three transport parameters (kP, kL, kCL), increasing kL over two orders of magnitude about the control value resulted in the greatest fluctuations in steady-state concentrations: most significantly elevating plasma VEGF and sVEGFR1, while lowering interstitial sVEGFR1. Exceptions were noted with localized changes in kL – e.g., with increasing only kL,Normal from ‘CP’ to ‘PE’, the enhanced flushing of sVEGFR1 from the local interstitium into the plasma eventually spilled over through increased sVEGFR1 extravasation into the opposite compartment to elevate interstitial sVEGFR1 concentration there. In addition, a reversal in permeability flow of sVEGFR1-VEGF complex (red box) was noted for kL above control. ‘Lo’ = low; ‘Nite’ = night; ‘+’ = supine awake (control); ‘SE’ = whole-body steady exercise; ‘CP’ = calf-only peak exercise; ‘PE’ = whole-body peak exercise; ‘Hi’ = high. Dynamic Effects of kL on VEGF, sVEGFR1, and sR1-VEGF Concentrations (C). kL-driven fluctuations in VEGF and sVEGFR1 attained within physiological diurnal cycles were less than those attained during steady-state analyses but still were of very wide ranges. “Bed-rest days” (purple columns) consisted of 15 hrs of wakefulness limited to supine or sitting postures, followed by 9 hrs of sleep. “Active days” (yellow columns) consisted of 15-hrs of activity starting off with a peak in kL during early exercise and settling down to a steady running/walking rate, followed by 9 hrs of sleep. Reversed permeability flow of sVEGFR1-VEGF complex (red cross-hatching) was observed in the latter active waking hours. “Calf-limited activity days” (aqua column) are same as “bed-rest days” except that active kL was induced in the calf during the first 15 hrs of wakefulness. Stick-figure illustrations adapted from Olszewski et al. Lymphology 1977, 10(3):178–183.
Mentions: Transport parameters were independently varied over two orders of magnitude about control for sensitivity analysis. In plasma, steady-state concentrations of all soluble species were strongly dependent on transport rates, whereas in the interstitium, sVEGFR1 concentration was much more sensitive than VEGF to transport parameters. In general: increasing kP reduced plasma vs. interstitium gradients (i.e., closer to 1∶1) for both VEGF and sVEGFR1 concentrations (Fig. 8A); increasing kL lessened VEGF gradients but steepened sVEGFR1 gradients (Fig. 9A); while decreasing kCL reduced VEGF gradients without much effect on sVEGFR1 gradients (Fig. 10). Additionally, the current model showed that physiological fluctuations in transport parameters were ineffective in altering endothelial VEGFR occupancy, given their minute effect on interstitial free VEGF levels.

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