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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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Blood VEGF, but not tissue VEGF concentration, is dependent on VEGF clearance and vascular permeability. The diseased compartment is not included here. A, Tissue and blood VEGF concentrations increase with VEGF secretion rate. The profile is approximately linear in each case. In the absence of VEGF clearance from the blood, the steady-state free VEGF concentration is the same in the tissue and in the blood (purple line). With a clearance rate of cV = 0.0206 min-1, the blood concentration (red line) is lower than that of the normal tissue (blue dots), which is unchanged by the clearance. Increase in tissue-blood permeability from kp = 4 × 10-8 cm/s (dotted line) to 4 × 10-7 cm/s (dashed line), raises the blood VEGF concentration but not the tissue concentration. B, Increasing transcapillary permeability increases the blood VEGF concentration at steady state. VEGF165 secretion rate q = 0.102 molecule/cell/s, clearance rate cV = 0.0206 min-1 [28]. C, Increased clearance rate of VEGF from the blood decreases blood concentration of VEGF, without decreasing tissue VEGF. VEGF165 secretion rate q = 0.102 molecule/cell/s, vascular permeabilities kp = 4 × 10-8 cm/s (dotted line) and 4 × 10-7 cm/s (dashed line). For all simulations, VEGFR1 = 10,000, VEGFR2 = 10,000 and NRP1 = 10,000 molecules/endothelial cell.
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Figure 2: Blood VEGF, but not tissue VEGF concentration, is dependent on VEGF clearance and vascular permeability. The diseased compartment is not included here. A, Tissue and blood VEGF concentrations increase with VEGF secretion rate. The profile is approximately linear in each case. In the absence of VEGF clearance from the blood, the steady-state free VEGF concentration is the same in the tissue and in the blood (purple line). With a clearance rate of cV = 0.0206 min-1, the blood concentration (red line) is lower than that of the normal tissue (blue dots), which is unchanged by the clearance. Increase in tissue-blood permeability from kp = 4 × 10-8 cm/s (dotted line) to 4 × 10-7 cm/s (dashed line), raises the blood VEGF concentration but not the tissue concentration. B, Increasing transcapillary permeability increases the blood VEGF concentration at steady state. VEGF165 secretion rate q = 0.102 molecule/cell/s, clearance rate cV = 0.0206 min-1 [28]. C, Increased clearance rate of VEGF from the blood decreases blood concentration of VEGF, without decreasing tissue VEGF. VEGF165 secretion rate q = 0.102 molecule/cell/s, vascular permeabilities kp = 4 × 10-8 cm/s (dotted line) and 4 × 10-7 cm/s (dashed line). For all simulations, VEGFR1 = 10,000, VEGFR2 = 10,000 and NRP1 = 10,000 molecules/endothelial cell.

Mentions: A range from 0.02 to 0.20 molecule/cell/s was tested for VEGF165 secretion rate. In the absence of plasma clearance, the free VEGF concentration in both compartments is close to directly proportional (R2 = 0.9973) to the VEGF secretion rate in the normal tissue for the range we tested (Figure 2A). In the absence of plasma clearance, the steady-state total VEGF concentration in the blood plasma equals that in the available interstitial fluid of the healthy tissue (i.e., diffusible VEGF contained in the accessible part of the fluid in the healthy tissue). This is in agreement with V equation (26) which, at steady state, becomes . If 1 pM (1 pmole/L of available interstitial fluid) of free VEGF concentration is present, at steady state, in the normal tissue available interstitial fluid, a VEGF concentration in the blood will also be 1 pM (1 pmole/L of blood plasma).


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)

Blood VEGF, but not tissue VEGF concentration, is dependent on VEGF clearance and vascular permeability. The diseased compartment is not included here. A, Tissue and blood VEGF concentrations increase with VEGF secretion rate. The profile is approximately linear in each case. In the absence of VEGF clearance from the blood, the steady-state free VEGF concentration is the same in the tissue and in the blood (purple line). With a clearance rate of cV = 0.0206 min-1, the blood concentration (red line) is lower than that of the normal tissue (blue dots), which is unchanged by the clearance. Increase in tissue-blood permeability from kp = 4 × 10-8 cm/s (dotted line) to 4 × 10-7 cm/s (dashed line), raises the blood VEGF concentration but not the tissue concentration. B, Increasing transcapillary permeability increases the blood VEGF concentration at steady state. VEGF165 secretion rate q = 0.102 molecule/cell/s, clearance rate cV = 0.0206 min-1 [28]. C, Increased clearance rate of VEGF from the blood decreases blood concentration of VEGF, without decreasing tissue VEGF. VEGF165 secretion rate q = 0.102 molecule/cell/s, vascular permeabilities kp = 4 × 10-8 cm/s (dotted line) and 4 × 10-7 cm/s (dashed line). For all simulations, VEGFR1 = 10,000, VEGFR2 = 10,000 and NRP1 = 10,000 molecules/endothelial cell.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2562372&req=5

Figure 2: Blood VEGF, but not tissue VEGF concentration, is dependent on VEGF clearance and vascular permeability. The diseased compartment is not included here. A, Tissue and blood VEGF concentrations increase with VEGF secretion rate. The profile is approximately linear in each case. In the absence of VEGF clearance from the blood, the steady-state free VEGF concentration is the same in the tissue and in the blood (purple line). With a clearance rate of cV = 0.0206 min-1, the blood concentration (red line) is lower than that of the normal tissue (blue dots), which is unchanged by the clearance. Increase in tissue-blood permeability from kp = 4 × 10-8 cm/s (dotted line) to 4 × 10-7 cm/s (dashed line), raises the blood VEGF concentration but not the tissue concentration. B, Increasing transcapillary permeability increases the blood VEGF concentration at steady state. VEGF165 secretion rate q = 0.102 molecule/cell/s, clearance rate cV = 0.0206 min-1 [28]. C, Increased clearance rate of VEGF from the blood decreases blood concentration of VEGF, without decreasing tissue VEGF. VEGF165 secretion rate q = 0.102 molecule/cell/s, vascular permeabilities kp = 4 × 10-8 cm/s (dotted line) and 4 × 10-7 cm/s (dashed line). For all simulations, VEGFR1 = 10,000, VEGFR2 = 10,000 and NRP1 = 10,000 molecules/endothelial cell.
Mentions: A range from 0.02 to 0.20 molecule/cell/s was tested for VEGF165 secretion rate. In the absence of plasma clearance, the free VEGF concentration in both compartments is close to directly proportional (R2 = 0.9973) to the VEGF secretion rate in the normal tissue for the range we tested (Figure 2A). In the absence of plasma clearance, the steady-state total VEGF concentration in the blood plasma equals that in the available interstitial fluid of the healthy tissue (i.e., diffusible VEGF contained in the accessible part of the fluid in the healthy tissue). This is in agreement with V equation (26) which, at steady state, becomes . If 1 pM (1 pmole/L of available interstitial fluid) of free VEGF concentration is present, at steady state, in the normal tissue available interstitial fluid, a VEGF concentration in the blood will also be 1 pM (1 pmole/L of blood plasma).

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