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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: John M Lyons 3rd, 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
• Journal: The Journal of surgical research (J Surg Res) Vol. 159 Issue 1 Pg. 517-27 (Mar 2010) ISSN: 1095-8673 [Electronic] United States
• PMID: 19577260 (Publication Type: Journal Article)
• Copyright: Copyright (c) 2010 Elsevier Inc. All rights reserved.

Chemical References

• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Fibrin
• Thrombin

Topics

• Cells, Cultured
• Endothelial Cells (metabolism)
• Fibrin
• Humans
• In Vitro Techniques
• Neovascularization, Pathologic
• Neovascularization, Physiologic
• Signal Transduction
• Thrombin
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, metabolism)