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A compartment model of VEGF distribution in blood, healthy and diseased tissues.

Stefanini MO, Wu FT, Mac Gabhann F, Popel AS - BMC Syst Biol (2008)

Bottom Line: Finally, the VEGF distribution profile in healthy tissue reveals that about half of the VEGF is complexed with the receptor tyrosine kinase VEGFR2 and the co-receptor Neuropilin-1.In diseased tissues, this binding can be reduced to 15% while VEGF bound to the extracellular matrix and basement membranes increases.This mathematical model can serve as a tool for understanding the VEGF distribution in physiological and pathological contexts as well as a foundation to investigate pro- or anti-angiogenic strategies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA. stefanini@jhmi.edu

ABSTRACT

Background: Angiogenesis is a process by which new capillaries are formed from pre-existing blood vessels in physiological (e.g., exercise, wound healing) or pathological (e.g., ischemic limb as in peripheral arterial disease, cancer) contexts. This neovascular mechanism is mediated by the vascular endothelial growth factor (VEGF) family of cytokines. Although VEGF is often targeted in anti-angiogenic therapies, there is little knowledge about how its concentration may vary between tissues and the vascular system. A compartment model is constructed to study the VEGF distribution in the tissue (including matrix-bound, cell surface receptor-bound and free VEGF isoforms) and in the blood. We analyze the sensitivity of this distribution to the secretion rate, clearance rate and vascular permeability of VEGF.

Results: We find that, in a physiological context, VEGF concentration varies approximately linearly with the VEGF secretion rate. VEGF concentration in blood but not in tissue is dependent on the vascular permeability of healthy tissue. Model simulations suggest that relative VEGF increases are similar in blood and tissue during exercise and return to baseline within several hours. In a pathological context (tumor), we find that blood VEGF concentration is relatively insensitive to increased vascular permeability in tumors, to the secretion rate of VEGF by tumors and to the clearance. However, it is sensitive to the vascular permeability in the healthy tissue. Finally, the VEGF distribution profile in healthy tissue reveals that about half of the VEGF is complexed with the receptor tyrosine kinase VEGFR2 and the co-receptor Neuropilin-1. In diseased tissues, this binding can be reduced to 15% while VEGF bound to the extracellular matrix and basement membranes increases.

Conclusion: The results are of importance for physiological conditions (e.g., exercise) and pathological conditions (e.g., peripheral arterial disease, coronary artery disease, cancer). This mathematical model can serve as a tool for understanding the VEGF distribution in physiological and pathological contexts as well as a foundation to investigate pro- or anti-angiogenic strategies.

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Compartment model of VEGF transport in blood and tissues. A, Schematic of a tissue cross section. VEGF165 can bind to glycosaminoglycan chains (GAG) and be sequestered in the extracellular matrix whereas VEGF121 cannot. The isoforms have different cell surface receptor binding profiles. B, Compartment model set-up. Three compartments are used in our simulations: blood, healthy and diseased tissues. The diseased tissue compartment is not used in all simulations. VEGF is secreted by parenchymal cells in the healthy and diseased compartments (q). VEGF transport between the blood and the tissue compartments is via transcapillary permeability (kp). VEGF receptors are expressed on the abluminal side of the endothelial cells and VEGF binding to these receptors can lead to internalization (kint). Plasma clearance for VEGF is present in the blood compartment (cV). C, Interactions between VEGF, cell surface receptors, extracellular matrix and basement membranes. VEGF121 binds to VEGFR2 but does not bind to NRP1. VEGF165 interacts with VEGFR2 or NRP1. Once bound, it can form a ternary complex VEGFR2- VEGF165- NRP1. VEGF165 can be sequestered by the ECM, PBM or EBM by binding to GAG chains. VEGF121 binds to VEGFR1. This receptor couples with NRP1 to form VEGFR1-NRP1 complex or the ternary complex VEGF121-VEGFR1-NRP1 if previously occupied by VEGF121. VEGF165 also binds to VEGFR1 but not to the VEGFR1-NRP1 complex. The receptors (VEGFR1, VEGFR2 and NRP1) are inserted or internalized at the cell surface.
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Figure 1: Compartment model of VEGF transport in blood and tissues. A, Schematic of a tissue cross section. VEGF165 can bind to glycosaminoglycan chains (GAG) and be sequestered in the extracellular matrix whereas VEGF121 cannot. The isoforms have different cell surface receptor binding profiles. B, Compartment model set-up. Three compartments are used in our simulations: blood, healthy and diseased tissues. The diseased tissue compartment is not used in all simulations. VEGF is secreted by parenchymal cells in the healthy and diseased compartments (q). VEGF transport between the blood and the tissue compartments is via transcapillary permeability (kp). VEGF receptors are expressed on the abluminal side of the endothelial cells and VEGF binding to these receptors can lead to internalization (kint). Plasma clearance for VEGF is present in the blood compartment (cV). C, Interactions between VEGF, cell surface receptors, extracellular matrix and basement membranes. VEGF121 binds to VEGFR2 but does not bind to NRP1. VEGF165 interacts with VEGFR2 or NRP1. Once bound, it can form a ternary complex VEGFR2- VEGF165- NRP1. VEGF165 can be sequestered by the ECM, PBM or EBM by binding to GAG chains. VEGF121 binds to VEGFR1. This receptor couples with NRP1 to form VEGFR1-NRP1 complex or the ternary complex VEGF121-VEGFR1-NRP1 if previously occupied by VEGF121. VEGF165 also binds to VEGFR1 but not to the VEGFR1-NRP1 complex. The receptors (VEGFR1, VEGFR2 and NRP1) are inserted or internalized at the cell surface.

Mentions: As a first approximation, a tissue can be represented as a collection of capillaries (and small arterioles and venules), surrounded by parenchymal cells. For example, skeletal muscle is constituted of long fibers whose cross sections are approximately constant. A schematic of this configuration is shown in Figure 1A. Note that the stromal cells are not considered explicitly in the model, but rather lumped with parenchymal cells. Between the parenchymal cells and the capillaries lies the interstitial space composed of the extracellular matrix (ECM), parenchymal basement membranes (PBM) and endothelial basement membranes (EBM). In this study, these anatomical structures will be represented in a spatially-averaged manner: each structure will be represented by a distinct volume with specific VEGF binding properties, but VEGF gradients within the volume will not be considered.


A compartment model of VEGF distribution in blood, healthy and diseased tissues.

Stefanini MO, Wu FT, Mac Gabhann F, Popel AS - BMC Syst Biol (2008)

Compartment model of VEGF transport in blood and tissues. A, Schematic of a tissue cross section. VEGF165 can bind to glycosaminoglycan chains (GAG) and be sequestered in the extracellular matrix whereas VEGF121 cannot. The isoforms have different cell surface receptor binding profiles. B, Compartment model set-up. Three compartments are used in our simulations: blood, healthy and diseased tissues. The diseased tissue compartment is not used in all simulations. VEGF is secreted by parenchymal cells in the healthy and diseased compartments (q). VEGF transport between the blood and the tissue compartments is via transcapillary permeability (kp). VEGF receptors are expressed on the abluminal side of the endothelial cells and VEGF binding to these receptors can lead to internalization (kint). Plasma clearance for VEGF is present in the blood compartment (cV). C, Interactions between VEGF, cell surface receptors, extracellular matrix and basement membranes. VEGF121 binds to VEGFR2 but does not bind to NRP1. VEGF165 interacts with VEGFR2 or NRP1. Once bound, it can form a ternary complex VEGFR2- VEGF165- NRP1. VEGF165 can be sequestered by the ECM, PBM or EBM by binding to GAG chains. VEGF121 binds to VEGFR1. This receptor couples with NRP1 to form VEGFR1-NRP1 complex or the ternary complex VEGF121-VEGFR1-NRP1 if previously occupied by VEGF121. VEGF165 also binds to VEGFR1 but not to the VEGFR1-NRP1 complex. The receptors (VEGFR1, VEGFR2 and NRP1) are inserted or internalized at the cell surface.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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Figure 1: Compartment model of VEGF transport in blood and tissues. A, Schematic of a tissue cross section. VEGF165 can bind to glycosaminoglycan chains (GAG) and be sequestered in the extracellular matrix whereas VEGF121 cannot. The isoforms have different cell surface receptor binding profiles. B, Compartment model set-up. Three compartments are used in our simulations: blood, healthy and diseased tissues. The diseased tissue compartment is not used in all simulations. VEGF is secreted by parenchymal cells in the healthy and diseased compartments (q). VEGF transport between the blood and the tissue compartments is via transcapillary permeability (kp). VEGF receptors are expressed on the abluminal side of the endothelial cells and VEGF binding to these receptors can lead to internalization (kint). Plasma clearance for VEGF is present in the blood compartment (cV). C, Interactions between VEGF, cell surface receptors, extracellular matrix and basement membranes. VEGF121 binds to VEGFR2 but does not bind to NRP1. VEGF165 interacts with VEGFR2 or NRP1. Once bound, it can form a ternary complex VEGFR2- VEGF165- NRP1. VEGF165 can be sequestered by the ECM, PBM or EBM by binding to GAG chains. VEGF121 binds to VEGFR1. This receptor couples with NRP1 to form VEGFR1-NRP1 complex or the ternary complex VEGF121-VEGFR1-NRP1 if previously occupied by VEGF121. VEGF165 also binds to VEGFR1 but not to the VEGFR1-NRP1 complex. The receptors (VEGFR1, VEGFR2 and NRP1) are inserted or internalized at the cell surface.
Mentions: As a first approximation, a tissue can be represented as a collection of capillaries (and small arterioles and venules), surrounded by parenchymal cells. For example, skeletal muscle is constituted of long fibers whose cross sections are approximately constant. A schematic of this configuration is shown in Figure 1A. Note that the stromal cells are not considered explicitly in the model, but rather lumped with parenchymal cells. Between the parenchymal cells and the capillaries lies the interstitial space composed of the extracellular matrix (ECM), parenchymal basement membranes (PBM) and endothelial basement membranes (EBM). In this study, these anatomical structures will be represented in a spatially-averaged manner: each structure will be represented by a distinct volume with specific VEGF binding properties, but VEGF gradients within the volume will not be considered.

Bottom Line: Finally, the VEGF distribution profile in healthy tissue reveals that about half of the VEGF is complexed with the receptor tyrosine kinase VEGFR2 and the co-receptor Neuropilin-1.In diseased tissues, this binding can be reduced to 15% while VEGF bound to the extracellular matrix and basement membranes increases.This mathematical model can serve as a tool for understanding the VEGF distribution in physiological and pathological contexts as well as a foundation to investigate pro- or anti-angiogenic strategies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA. stefanini@jhmi.edu

ABSTRACT

Background: Angiogenesis is a process by which new capillaries are formed from pre-existing blood vessels in physiological (e.g., exercise, wound healing) or pathological (e.g., ischemic limb as in peripheral arterial disease, cancer) contexts. This neovascular mechanism is mediated by the vascular endothelial growth factor (VEGF) family of cytokines. Although VEGF is often targeted in anti-angiogenic therapies, there is little knowledge about how its concentration may vary between tissues and the vascular system. A compartment model is constructed to study the VEGF distribution in the tissue (including matrix-bound, cell surface receptor-bound and free VEGF isoforms) and in the blood. We analyze the sensitivity of this distribution to the secretion rate, clearance rate and vascular permeability of VEGF.

Results: We find that, in a physiological context, VEGF concentration varies approximately linearly with the VEGF secretion rate. VEGF concentration in blood but not in tissue is dependent on the vascular permeability of healthy tissue. Model simulations suggest that relative VEGF increases are similar in blood and tissue during exercise and return to baseline within several hours. In a pathological context (tumor), we find that blood VEGF concentration is relatively insensitive to increased vascular permeability in tumors, to the secretion rate of VEGF by tumors and to the clearance. However, it is sensitive to the vascular permeability in the healthy tissue. Finally, the VEGF distribution profile in healthy tissue reveals that about half of the VEGF is complexed with the receptor tyrosine kinase VEGFR2 and the co-receptor Neuropilin-1. In diseased tissues, this binding can be reduced to 15% while VEGF bound to the extracellular matrix and basement membranes increases.

Conclusion: The results are of importance for physiological conditions (e.g., exercise) and pathological conditions (e.g., peripheral arterial disease, coronary artery disease, cancer). This mathematical model can serve as a tool for understanding the VEGF distribution in physiological and pathological contexts as well as a foundation to investigate pro- or anti-angiogenic strategies.

Show MeSH
Related in: MedlinePlus