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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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Distribution of VEGF and its receptors for each tissue. The diseased compartment represents a 4-cm diameter tumor. Vascular permeability of healthy tissue,  = 4 × 10-8 cm/s; vascular permeability of the tumor  = 4 × 10-7 cm/s; VEGF plasma clearance cV = 0.0206 min-1 [28]; VEGFR1 = 10,000 and VEGFR2 = 10,000 molecules/endothelial cell; NRP1 = 10,000 molecules/endothelial cell in the healthy tissue; VEGF165 secretion rate in healthy tissue qN = 0.102 molecule/cell/s; tumor VEGF165 secretion rate qD = 0.076 or 0.025 molecule/cell/s for 10,000 (written in black) or 100,000 (written in dark yellow) NRP1 in tumor respectively. A, From center out, discs represent: total VEGF, VEGF121 and VEGF165 distributions. In the healthy tissue, about half of the total VEGF distribution is in the form of the ternary complex VEGF165 bound to VEGFR2 and NRP1, leaving 24% bound to the ECM. In the tumor, most total VEGF is bound to the ECM (68% and 41% for 10,000 and 100,000 NRP1 in tumor, respectively). Most of the remaining total VEGF population is in the form of the ternary complex VEGF165 bound to VEGFR2 and NRP1 (15% and 48% for 10,000 and 100,000 NRP1 in tumor, respectively). Most of VEGF121 isoform is bound to VEGFR1 and NRP1 simultaneously. The vast majority of the free VEGF distribution in the blood is in the isoform VEGF165 (91%). B, Receptor occupancy. From center out, discs represent: overall receptor, NRP1, VEGFR2, VEGFR1 occupancies. The initial receptor densities dictate the receptor occupancies. For identical NRP1 receptor densities (10,000), the healthy tissue and the tumor have the same receptor occupancies: 60% of all the receptors are in their free states and 33% are in the complex form VEGFR1-NRP1. If the NRP1 density is increased by 10-fold in the tumor, most of the total receptors are free NRP1 (81%) and a small fraction is bound to VEGFR1 (9%).
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Figure 5: Distribution of VEGF and its receptors for each tissue. The diseased compartment represents a 4-cm diameter tumor. Vascular permeability of healthy tissue, = 4 × 10-8 cm/s; vascular permeability of the tumor = 4 × 10-7 cm/s; VEGF plasma clearance cV = 0.0206 min-1 [28]; VEGFR1 = 10,000 and VEGFR2 = 10,000 molecules/endothelial cell; NRP1 = 10,000 molecules/endothelial cell in the healthy tissue; VEGF165 secretion rate in healthy tissue qN = 0.102 molecule/cell/s; tumor VEGF165 secretion rate qD = 0.076 or 0.025 molecule/cell/s for 10,000 (written in black) or 100,000 (written in dark yellow) NRP1 in tumor respectively. A, From center out, discs represent: total VEGF, VEGF121 and VEGF165 distributions. In the healthy tissue, about half of the total VEGF distribution is in the form of the ternary complex VEGF165 bound to VEGFR2 and NRP1, leaving 24% bound to the ECM. In the tumor, most total VEGF is bound to the ECM (68% and 41% for 10,000 and 100,000 NRP1 in tumor, respectively). Most of the remaining total VEGF population is in the form of the ternary complex VEGF165 bound to VEGFR2 and NRP1 (15% and 48% for 10,000 and 100,000 NRP1 in tumor, respectively). Most of VEGF121 isoform is bound to VEGFR1 and NRP1 simultaneously. The vast majority of the free VEGF distribution in the blood is in the isoform VEGF165 (91%). B, Receptor occupancy. From center out, discs represent: overall receptor, NRP1, VEGFR2, VEGFR1 occupancies. The initial receptor densities dictate the receptor occupancies. For identical NRP1 receptor densities (10,000), the healthy tissue and the tumor have the same receptor occupancies: 60% of all the receptors are in their free states and 33% are in the complex form VEGFR1-NRP1. If the NRP1 density is increased by 10-fold in the tumor, most of the total receptors are free NRP1 (81%) and a small fraction is bound to VEGFR1 (9%).

Mentions: In the above sections, we presented results of computer simulations for free VEGF in the tissue and blood compartments. To understand the total balance of VEGF in the body, it is also important to assess the amounts of VEGF bound to the receptors on the endothelial cells and to the HSPG sites in the ECM and basement membranes. The VEGF distribution is shown in Figure 5A. For the parameters specified in the legend, 93% of total VEGF in the healthy tissue is VEGF165. The model revealed that up to half of the VEGF distribution in the healthy tissue and the tumor with 100,000 NRP1 per endothelial cell, is in the form of a complex where VEGF165 is bound to VEGFR2 and NRP1 simultaneously. In the tumor, 41 to 68% (depending on the NRP1 density) of the VEGF population, is VEGF165 bound to the ECM while it represented only a quarter in the healthy tissue. Finally, the vast majority of free VEGF in the blood is VEGF165 (91%), regardless of the density of NRP1 in the tumor.


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)

Distribution of VEGF and its receptors for each tissue. The diseased compartment represents a 4-cm diameter tumor. Vascular permeability of healthy tissue,  = 4 × 10-8 cm/s; vascular permeability of the tumor  = 4 × 10-7 cm/s; VEGF plasma clearance cV = 0.0206 min-1 [28]; VEGFR1 = 10,000 and VEGFR2 = 10,000 molecules/endothelial cell; NRP1 = 10,000 molecules/endothelial cell in the healthy tissue; VEGF165 secretion rate in healthy tissue qN = 0.102 molecule/cell/s; tumor VEGF165 secretion rate qD = 0.076 or 0.025 molecule/cell/s for 10,000 (written in black) or 100,000 (written in dark yellow) NRP1 in tumor respectively. A, From center out, discs represent: total VEGF, VEGF121 and VEGF165 distributions. In the healthy tissue, about half of the total VEGF distribution is in the form of the ternary complex VEGF165 bound to VEGFR2 and NRP1, leaving 24% bound to the ECM. In the tumor, most total VEGF is bound to the ECM (68% and 41% for 10,000 and 100,000 NRP1 in tumor, respectively). Most of the remaining total VEGF population is in the form of the ternary complex VEGF165 bound to VEGFR2 and NRP1 (15% and 48% for 10,000 and 100,000 NRP1 in tumor, respectively). Most of VEGF121 isoform is bound to VEGFR1 and NRP1 simultaneously. The vast majority of the free VEGF distribution in the blood is in the isoform VEGF165 (91%). B, Receptor occupancy. From center out, discs represent: overall receptor, NRP1, VEGFR2, VEGFR1 occupancies. The initial receptor densities dictate the receptor occupancies. For identical NRP1 receptor densities (10,000), the healthy tissue and the tumor have the same receptor occupancies: 60% of all the receptors are in their free states and 33% are in the complex form VEGFR1-NRP1. If the NRP1 density is increased by 10-fold in the tumor, most of the total receptors are free NRP1 (81%) and a small fraction is bound to VEGFR1 (9%).
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Figure 5: Distribution of VEGF and its receptors for each tissue. The diseased compartment represents a 4-cm diameter tumor. Vascular permeability of healthy tissue, = 4 × 10-8 cm/s; vascular permeability of the tumor = 4 × 10-7 cm/s; VEGF plasma clearance cV = 0.0206 min-1 [28]; VEGFR1 = 10,000 and VEGFR2 = 10,000 molecules/endothelial cell; NRP1 = 10,000 molecules/endothelial cell in the healthy tissue; VEGF165 secretion rate in healthy tissue qN = 0.102 molecule/cell/s; tumor VEGF165 secretion rate qD = 0.076 or 0.025 molecule/cell/s for 10,000 (written in black) or 100,000 (written in dark yellow) NRP1 in tumor respectively. A, From center out, discs represent: total VEGF, VEGF121 and VEGF165 distributions. In the healthy tissue, about half of the total VEGF distribution is in the form of the ternary complex VEGF165 bound to VEGFR2 and NRP1, leaving 24% bound to the ECM. In the tumor, most total VEGF is bound to the ECM (68% and 41% for 10,000 and 100,000 NRP1 in tumor, respectively). Most of the remaining total VEGF population is in the form of the ternary complex VEGF165 bound to VEGFR2 and NRP1 (15% and 48% for 10,000 and 100,000 NRP1 in tumor, respectively). Most of VEGF121 isoform is bound to VEGFR1 and NRP1 simultaneously. The vast majority of the free VEGF distribution in the blood is in the isoform VEGF165 (91%). B, Receptor occupancy. From center out, discs represent: overall receptor, NRP1, VEGFR2, VEGFR1 occupancies. The initial receptor densities dictate the receptor occupancies. For identical NRP1 receptor densities (10,000), the healthy tissue and the tumor have the same receptor occupancies: 60% of all the receptors are in their free states and 33% are in the complex form VEGFR1-NRP1. If the NRP1 density is increased by 10-fold in the tumor, most of the total receptors are free NRP1 (81%) and a small fraction is bound to VEGFR1 (9%).
Mentions: In the above sections, we presented results of computer simulations for free VEGF in the tissue and blood compartments. To understand the total balance of VEGF in the body, it is also important to assess the amounts of VEGF bound to the receptors on the endothelial cells and to the HSPG sites in the ECM and basement membranes. The VEGF distribution is shown in Figure 5A. For the parameters specified in the legend, 93% of total VEGF in the healthy tissue is VEGF165. The model revealed that up to half of the VEGF distribution in the healthy tissue and the tumor with 100,000 NRP1 per endothelial cell, is in the form of a complex where VEGF165 is bound to VEGFR2 and NRP1 simultaneously. In the tumor, 41 to 68% (depending on the NRP1 density) of the VEGF population, is VEGF165 bound to the ECM while it represented only a quarter in the healthy tissue. Finally, the vast majority of free VEGF in the blood is VEGF165 (91%), regardless of the density of NRP1 in the tumor.

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