The role of VEGF pathways in human physiologic and pathologic angiogenesis.

John M Lyons, Joshua E Schwimer, Catherine T Anthony, Jessica L Thomson, Jason D Cundiff, Douglas T Casey, Cynthia Maccini, Paul Kucera, Yi-Zarn Wang, J Philip Boudreaux, Eugene A Woltering

Louisiana State University Health Sciences Center Department of Surgery, Section of Surgical Oncology and Section of Surgical Endocrinology, Kenner, Louisiana 70065, USA.

The Journal of surgical research 2010 Mar

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In preclinical models, VEGF is a potent stimulant of both physiologic and pathologic angiogenesis. Conversely, anti-VEGF regimens have successfully inhibited angiogenesis both in vitro and in vivo. We hypothesized that VEGF would stimulate both physiologic and pathologic angiogenesis in a human-based fibrin-thrombin clot angiogenesis assay. We further speculated that anti-VEGF regimens would inhibit angiogenesis in this assay. To test these hypotheses, discs of human placental veins (physiologic model) and fragments of human tumors (pathologic model) were embedded in fibrin-thrombin clots and treated with either VEGF-A165 (VEGF) or anti-VEGF pathway reagents including bevacizumab, IMC-18F1, IMC-1121, and PTK787 (n=30 wells per treatment group, multiple concentrations tested in each specimen). Angiogenic responses were assessed visually using a previously validated grading scheme. The percent of tissue explants that developed angiogenic invasion into the clot (% I) as well as the extent of angiogenic growth (AI) via a semi-quantitative scale were assessed at set intervals. VEGF failed to stimulate angiogenesis in both the physiologic and the pathologic model. While anti-VEGF reagents that targeted only one element of the VEGF pathway failed to consistently inhibit angiogenesis, PTK787, a receptor tyrosine kinase inhibitor that targets multiple VEGF and non-VEGF receptors, profoundly inhibited both physiologic and pathologic angiogenesis. These results suggest that VEGF-related pathways may not be solely responsible for stimulating angiogenesis in humans. Targeting the VEGF pathway in combination with elements of other growth factor pathways may provide a more effective means of inhibiting angiogenesis than targeting VEGF alone. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Citation

John M Lyons, Joshua E Schwimer, Catherine T Anthony, Jessica L Thomson, Jason D Cundiff, Douglas T Casey, Cynthia Maccini, Paul Kucera, Yi-Zarn Wang, J Philip Boudreaux, Eugene A Woltering. The role of VEGF pathways in human physiologic and pathologic angiogenesis. The Journal of surgical research. 2010 Mar;159(1):517-27