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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 2007 (4)

Title and authors Publication Year
In Vitro Models of Angiogenesis
AA Ucuzian, HP Greisler
World Journal of Surgery 2007
Matrices and scaffolds for DNA delivery in tissue engineering
LD Laporte, LD Shea
Advanced Drug Delivery Reviews 2007
Proangiogenic Potential of a Collagen/Bioactive Glass Substrate
A Leu, JK Leach
Pharmaceutical Research 2007
Angiogenesis and vascular malformations: antiangiogenic drugs for treatment of gastrointestinal bleeding.
Bauditz J, Lochs H
World Journal of Gastroenterology 2007

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 42 patents
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