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Citations to this article

Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis
Clare R. Ozawa, … , Donald M. McDonald, Helen M. Blau
Clare R. Ozawa, … , Donald M. McDonald, Helen M. Blau
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):516-527. https://doi.org/10.1172/JCI18420.
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Article Cardiology Article has an altmetric score of 9

Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis

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Abstract

Use of long-term constitutive expression of VEGF for therapeutic angiogenesis may be limited by the growth of abnormal blood vessels and hemangiomas. We investigated the relationship between VEGF dosage and the morphology and function of newly formed blood vessels by implanting retrovirally transduced myoblasts that constitutively express VEGF164 into muscles of adult mice. Reducing VEGF dosage by decreasing the total number of VEGF myoblasts implanted did not prevent vascular abnormalities. However, when clonal populations of myoblasts homogeneously expressing different levels of VEGF were implanted, a threshold between normal and aberrant angiogenesis was found. Clonal myoblasts that expressed low to medium levels of VEGF induced growth of stable, pericyte-coated capillaries of uniform size that were not leaky and became VEGF independent, as shown by treatment with the potent VEGF blocker VEGF-TrapR1R2. In contrast, clones that expressed high levels of VEGF induced hemangiomas. Remarkably, when different clonal populations were mixed, even a small proportion of cells with high production of VEGF was sufficient to cause hemangioma growth. These results show for the first time to our knowledge that the key determinant of whether VEGF-induced angiogenesis is normal or aberrant is the microenvironmental amount of growth factor secreted, rather than the overall dose. Long-term continuous delivery of VEGF, when maintained below a threshold microenvironmental level, can lead to normal angiogenesis without other exogenous growth factors.

Authors

Clare R. Ozawa, Andrea Banfi, Nicole L. Glazer, Gavin Thurston, Matthew L. Springer, Peggy E. Kraft, Donald M. McDonald, Helen M. Blau

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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 Total
Citations: 5 5 4 8 14 12 8 9 9 12 14 9 10 13 12 18 11 7 4 7 8 1 200
Citation information
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Citations to this article in year 2012 (13)

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Therapeutic Angiogenesis Using Basic Fibroblast Growth Factor in Combination with a Collagen Matrix in Chronic Hindlimb Ischemia
J Zhou, Y Zhao, J Wang, S Zhang, Z Liu, M Zhen, Y Liu, P Liu, Z Yin, X Wang
The Scientific World JOURNAL 2012
Cationic lipid-coated PEI/DNA polyplexes with improved efficiency and reduced cytotoxicity for gene delivery into mesenchymal stem cells
H Song, G Wang, B He, L Li, C Li, Y Lai, X Xu, Z Gu
International Journal of Nanomedicine 2012
Tissue deformation spatially modulates VEGF signaling and angiogenesis
NC Rivron, EJ Vrij, J Rouwkema, SL Gac, A Berg, RK Truckenmüller, CA van Blitterswijk
Proceedings of the National Academy of Sciences 2012
Treatment of Mouse Limb Ischemia with an Integrative Hypoxia-Responsive Vector Expressing the Vascular Endothelial Growth Factor Gene
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PloS one 2012
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L Melly, S Boccardo, F Eckstein, A Banfi, A Marsano
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AS Salimath, EA Phelps, AV Boopathy, P Che, M Brown, AJ García, ME Davis
PloS one 2012
Skeletal myogenic differentiation of urine-derived stem cells and angiogenesis using microbeads loaded with growth factors
G Liu, RA Pareta, R Wu, Y Shi, X Zhou, H Liu, C Deng, X Sun, A Atala, EC Opara, Y Zhang
Biomaterials 2012
Controlled angiogenesis in the heart by cell-based expression of specific vascular endothelial growth factor levels
LF Melly, A Marsano, A Frobert, S Boccardo, U Helmrich, M Heberer, FS Eckstein, TP Carrel, MN Giraud, HT Tevaearai, A Banfi
Human Gene Therapy Methods 2012
Neovascularization in Tissue Engineering
JC Chung, D Shum-Tim
Cells 2012
Bone marrow stromal cells stimulate an angiogenic program that requires endothelial MT1-MMP
S Kachgal, B Carrion, IA Janson, AJ Putnam
Journal of Cellular Physiology 2012
Therapeutic angiogenesis due to balanced single-vector delivery of VEGF and PDGF-BB
A Banfi, G von Degenfeld, R Gianni-Barrera, S Reginato, MJ Merchant, DM McDonald, HM Blau
The FASEB Journal 2012

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