title: A multiscale computational model predicts distribution of anti-angiogenic isoform VEGF165bin peripheral arterial disease in human and mouse.
abstract: Angiogenesis is the growth of new blood vessels from pre-existing microvessels. Peripheral arterial disease (PAD) is caused by atherosclerosis that results in ischemia mostly in the lower extremities. Clinical trials including VEGF-A administration for therapeutic angiogenesis have not been successful. The existence of anti-angiogenic isoform (VEGF165b) in PAD muscle tissues is a potential cause for the failure of therapeutic angiogenesis. Experimental measurements show that in PAD human muscle biopsies the VEGF165bisoform is at least as abundant if not greater than the VEGF165aisoform. We constructed three-compartment models describing VEGF isoforms and receptors, in human and mouse, to make predictions on the secretion rate of VEGF165band the distribution of various isoforms throughout the body based on the experimental data. The computational results are consistent with the data showing that in PAD calf muscles secrete mostly VEGF165bover total VEGF. In the PAD calf compartment of human and mouse models, most VEGF165aand VEGF165bare bound to the extracellular matrix. VEGF receptors VEGFR1, VEGFR2 and Neuropilin-1 (NRP1) are mostly in 'Free State'. This study provides a computational model of VEGF165bin PAD supported by experimental measurements of VEGF165bin human and mouse, which gives insight of VEGF165bin therapeutic angiogenesis and VEGF distribution in human and mouse PAD model.
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, United States.
authors.forename: Liang-Hui
authors.initials: LH
authors.lastname: Chu
authors.affiliation: Cardiovascular Medicine, Department of Medicine, and the Robert M. Berne Cardiovascular Research Center University of Virginia School of Medicine, Charlottesville, VA 22901, United States.
authors.forename: Vijay Chaitanya
authors.initials: VC
authors.lastname: Ganta
authors.affiliation: Cardiovascular Medicine, Department of Medicine, and the Robert M. Berne Cardiovascular Research Center University of Virginia School of Medicine, Charlottesville, VA 22901, United States.
authors.forename: Min H
authors.initials: MH
authors.lastname: Choi
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, United States.
authors.forename: George
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States.
authors.forename: Stacey D
authors.initials: SD
authors.lastname: Finley
authors.affiliation: Cardiovascular Medicine, Department of Medicine, and the Robert M. Berne Cardiovascular Research Center University of Virginia School of Medicine, Charlottesville, VA 22901, United States.
authors.forename: Brian H
authors.initials: BH
authors.lastname: Annex
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, United States.
authors.forename: Aleksander S
authors.initials: AS
authors.lastname: Popel
mesh_terms: D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D000818:Animals; D003198:Computer Simulation; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D039942:Neuropilin-1 / Q000378:metabolism; D058729:Peripheral Arterial Disease / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism*; 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; D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2