title: A two-compartment model of VEGF distribution in the mouse.
abstract: Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis--the growth of new microvessels from existing microvasculature. Angiogenesis is a complex process involving numerous molecular species, and to better understand it, a systems biology approach is necessary. In vivo preclinical experiments in the area of angiogenesis are typically performed in mouse models; this includes drug development targeting VEGF. Thus, to quantitatively interpret such experimental results, a computational model of VEGF distribution in the mouse can be beneficial. In this paper, we present an in silico model of VEGF distribution in mice, determine model parameters from existing experimental data, conduct sensitivity analysis, and test the validity of the model. The multiscale model is comprised of two compartments: blood and tissue. The model accounts for interactions between two major VEGF isoforms (VEGF(120) and VEGF(164)) and their endothelial cell receptors VEGFR-1, VEGFR-2, and co-receptor neuropilin-1. Neuropilin-1 is also expressed on the surface of parenchymal cells. The model includes transcapillary macromolecular permeability, lymphatic transport, and macromolecular plasma clearance. Simulations predict that the concentration of unbound VEGF in the tissue is approximately 50-fold greater than in the blood. These concentrations are highly dependent on the VEGF secretion rate. Parameter estimation was performed to fit the simulation results to available experimental data, and permitted the estimation of VEGF secretion rate in healthy tissue, which is difficult to measure experimentally. The model can provide quantitative interpretation of preclinical animal data and may be used in conjunction with experimental studies in the development of pro- and anti-angiogenic agents. The model approximates the normal tissue as skeletal muscle and includes endothelial cells to represent the vasculature. As the VEGF system becomes better characterized in other tissues and cell types, the model can be expanded to include additional compartments and vascular elements.
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Phillip
authors.initials: P
authors.lastname: Yen
authors.forename: Stacey D
authors.initials: SD
authors.lastname: Finley
authors.forename: Marianne O
authors.initials: MO
authors.lastname: Engel-Stefanini
authors.forename: Aleksander S
authors.initials: AS
authors.lastname: Popel
mesh_terms: D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D000818:Animals; D001769:Blood; D051379:Mice; D008954:Models, Biological; D039942:Neuropilin-1 / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D039942:Neuropilin-1; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2
references.citation: J Appl Physiol (1985). 1987 Sep;63(3):1003-7
references.pmid: 3654450
references.citation: Am J Physiol Heart Circ Physiol. 2007 Jan;292(1):H459-74
references.pmid: 16980341
references.citation: Doc Ophthalmol. 1970 Jul 24;28(1):191-200
references.pmid: 5478356
references.citation: Cancer Res. 2010 Dec 1;70(23):9886-94
references.pmid: 21118974
references.citation: Microvasc Res. 1992 Jan;43(1):46-59
references.pmid: 1608339
references.citation: Endocr Rev. 1997 Feb;18(1):4-25
references.pmid: 9034784
references.citation: J Biomed Biotechnol. 2010;2010:137817
references.pmid: 20414335
references.citation: Microvasc Res. 1997 Mar;53(2):113-20
references.pmid: 9143542
references.citation: J Appl Physiol (1985). 2005 May;98(5):1626-9
references.pmid: 15649874
references.citation: FASEB J. 2007 Dec;21(14):3896-903
references.pmid: 17644610
references.citation: J Appl Physiol Respir Environ Exerc Physiol. 1977 May;42(5):731-4
references.pmid: 863841
references.citation: Pathol Int. 2002 May-Jun;52(5-6):331-9
references.pmid: 12100515
references.citation: Invest Ophthalmol Vis Sci. 1986 Nov;27(11):1653-8
references.pmid: 3771145
references.citation: J Biol Chem. 1992 Dec 25;267(36):26031-7
references.pmid: 1464614
references.citation: Pol J Pathol. 2003;54(1):53-9
references.pmid: 12817881
references.citation: J Physiol. 1982 Jul;328:507-19
references.pmid: 7131323
references.citation: Exp Physiol. 2005 May;90(3):403-9
references.pmid: 15708874
references.citation: J Cell Mol Med. 2010 Mar;14(3):528-52
references.pmid: 19840194
references.citation: Theor Biol Med Model. 2011 Apr 04;8:6
references.pmid: 21463529
references.citation: Anat Rec. 1999 Dec 1;256(4):425-32
references.pmid: 10589028
references.citation: PLoS Comput Biol. 2009 Dec;5(12):e1000622
references.pmid: 20041209
references.citation: Exp Cell Res. 2011 Apr 15;317(7):955-65
references.pmid: 21185287
references.citation: Respir Physiol. 1989 Jun;76(3):289-302
references.pmid: 2749029
references.citation: Am J Physiol. 1970 Dec;219(6):1595-605
references.pmid: 5485678
references.citation: Blood. 2008 Feb 1;111(3):1227-33
references.pmid: 17962514
references.citation: Crit Rev Oncol Hematol. 2007 Jun;62(3):179-213
references.pmid: 17324579
references.citation: Am J Physiol Heart Circ Physiol. 2010 Jun;298(6):H2174-91
references.pmid: 20382861
references.citation: Comp Biochem Physiol B. 1988;91(1):179-85
references.pmid: 3197391
references.citation: Math Med Biol. 2012 Mar;29(1):85-94
references.pmid: 21266494
references.citation: J Physiol. 2009 Apr 15;587(Pt 8):1755-67
references.pmid: 19237429
references.citation: Neurobiol Aging. 1983 Spring;4(1):69-75
references.pmid: 6877490
references.citation: J Cardiovasc Med (Hagerstown). 2008 Dec;9(12):1190-221
references.pmid: 19001927
references.citation: Mol Reprod Dev. 2001 Nov;60(3):351-61
references.pmid: 11599046
references.citation: Acta Histochem. 2002;104(4):399-405
references.pmid: 12553710
references.citation: Exp Physiol. 2009 Jan;94(1):117-29
references.pmid: 18820003
references.citation: Blood. 2006 Aug 15;108(4):1243-50
references.pmid: 16621967
references.citation: PLoS One. 2009;4(4):e5108
references.pmid: 19352513
references.citation: Invest Ophthalmol Vis Sci. 2003 Nov;44(11):4960-7
references.pmid: 14578423
references.citation: Nat Med. 1995 Jan;1(1):27-31
references.pmid: 7584949
references.citation: Int J Radiat Oncol Biol Phys. 2007 Apr 1;67(5):1526-37
references.pmid: 17234361
references.citation: Science. 1989 Dec 8;246(4935):1306-9
references.pmid: 2479986
references.citation: BMC Syst Biol. 2011 May 02;5:59
references.pmid: 21535871
references.citation: Biochem Biophys Res Commun. 1975 Sep 2;66(1):9-16
references.pmid: 1164441
references.citation: Physiol Genomics. 2004 Jun 17;18(1):63-9
references.pmid: 15084712
references.citation: Oncol Rep. 1998 Sep-Oct;5(5):1115-8
references.pmid: 9683819
references.citation: Am J Physiol Gastrointest Liver Physiol. 2000 Aug;279(2):G325-31
references.pmid: 10915641
references.citation: Head Face Med. 2010 Jul 19;6:17
references.pmid: 20642842
references.citation: Am J Physiol Renal Physiol. 2005 Apr;288(4):F605-13
references.pmid: 15753324
references.citation: J Clin Invest. 1937 May;16(3):317-28
references.pmid: 16694481
references.citation: EMBO J. 2003 Apr 15;22(8):1771-9
references.pmid: 12682010
references.citation: Nat Med. 2003 Jun;9(6):669-76
references.pmid: 12778165
references.citation: Clin Breast Cancer. 2012 Dec;12(6):387-91
references.pmid: 23083501
references.citation: J Histochem Cytochem. 2000 Apr;48(4):545-56
references.pmid: 10727296
references.citation: BMC Syst Biol. 2008 Aug 19;2:77
references.pmid: 18713470
references.citation: Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11393-8
references.pmid: 12177445
references.citation: J Appl Physiol (1985). 2009 May;106(5):1660-7
references.pmid: 19286572
references.citation: Acta Pathol Microbiol Scand. 1969;77(4):758-60
references.pmid: 5383844
references.citation: Acta Neurol Scand. 1976 Jul;54(1):45-56
references.pmid: 132838
references.citation: Ann Biomed Eng. 2004 May;32(5):645-63
references.pmid: 15171620
references.citation: Methods Enzymol. 2009;467:461-497
references.pmid: 19897104
references.citation: Braz J Med Biol Res. 2008 Sep;41(9):812-7
references.pmid: 18820772
references.citation: Dev Dyn. 2001 Feb;220(2):112-21
references.pmid: 11169844
references.citation: Ann Anat. 2011 Feb 20;193(1):56-63
references.pmid: 20833519
references.citation: J Biol Chem. 2003 Apr 11;278(15):12605-8
references.pmid: 12538598
references.citation: Experientia. 1966 Dec 15;22(12):792
references.pmid: 5973211
references.citation: Experientia. 1968 Dec 15;24(12):1203-4
references.pmid: 5703010
references.citation: J Appl Physiol (1985). 2006 Jun;100(6):2024-30
references.pmid: 16497845
references.citation: J Thorac Oncol. 2010 Jul;5(7):1054-9
references.pmid: 20593550
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18363-70
references.pmid: 18000042
references.citation: Pac Symp Biocomput. 2009;:316-27
references.pmid: 19209711
references.citation: Pol J Pathol. 2002;53(4):183-8
references.pmid: 12597334