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

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 n...

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Autores principales:	Florence T H Wu, Marianne O Stefanini, Feilim Mac Gabhann, Aleksander S Popel
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/535c8d177efe416582c1171d841a00ae
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spelling	oai:doaj.org-article:535c8d177efe416582c1171d841a00ae2021-11-25T06:16:14ZA compartment model of VEGF distribution in humans in the presence of soluble VEGF receptor-1 acting as a ligand trap.1932-620310.1371/journal.pone.0005108https://doaj.org/article/535c8d177efe416582c1171d841a00ae2009-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19352513/?tool=EBIhttps://doaj.org/toc/1932-6203Vascular 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.Florence T H WuMarianne O StefaniniFeilim Mac GabhannAleksander S PopelPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 4, Iss 4, p e5108 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Florence T H Wu Marianne O Stefanini Feilim Mac Gabhann Aleksander S Popel A compartment model of VEGF distribution in humans in the presence of soluble VEGF receptor-1 acting as a ligand trap.
description	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.
format	article
author	Florence T H Wu Marianne O Stefanini Feilim Mac Gabhann Aleksander S Popel
author_facet	Florence T H Wu Marianne O Stefanini Feilim Mac Gabhann Aleksander S Popel
author_sort	Florence T H Wu
title	A compartment model of VEGF distribution in humans in the presence of soluble VEGF receptor-1 acting as a ligand trap.
title_short	A compartment model of VEGF distribution in humans in the presence of soluble VEGF receptor-1 acting as a ligand trap.
title_full	A compartment model of VEGF distribution in humans in the presence of soluble VEGF receptor-1 acting as a ligand trap.
title_fullStr	A compartment model of VEGF distribution in humans in the presence of soluble VEGF receptor-1 acting as a ligand trap.
title_full_unstemmed	A compartment model of VEGF distribution in humans in the presence of soluble VEGF receptor-1 acting as a ligand trap.
title_sort	compartment model of vegf distribution in humans in the presence of soluble vegf receptor-1 acting as a ligand trap.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/535c8d177efe416582c1171d841a00ae
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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.

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