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Elevated Flk1 (Vascular Endothelial Growth Factor Receptor 2) Signaling Mediates Enhanced Angiogenesis in ß₃-Integrin–Deficient Mice

¹ Cell Adhesion and Disease Group, Tumour Biology Laboratory, Cancer Research UK Clinical Centre, Barts and the London, Queen Mary’s School of Medicine and Dentistry, John Vane Science Centre, London, United Kingdom; ² Genentech, Inc., South San Francisco, California; ³ Center for Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; ⁴ ImClone Systems, Inc., New York, New York; and ⁵ DNAX, Palo Alto, California

Tumor growth, tumor angiogenesis, and vascular endothelial growth factor (VEGF)–specific angiogenesis are all enhanced in ß₃-integrin–null mice. Furthermore, endothelial cells isolated from ß₃-null mice show elevated levels of Flk1 (VEGF receptor 2) expression, suggesting that ß₃-integrin can control the amplitude of VEGF responses by controlling Flk1 levels or activity. We now show that Flk1 signaling is required for the enhanced tumor growth and angiogenesis seen in ß₃-null mice. Moreover, ß₃-null endothelial cells exhibit enhanced migration and proliferation in response to VEGF in vitro, and this phenotype requires Flk1 signaling. Upon VEGF stimulation, ß₃-null endothelial cells exhibit higher levels of phosphorylated Flk1 and extracellular-related kinases 1 and 2 than wild-type endothelial cells. Furthermore, signaling via ERK1/2 is required to mediate the elevated responses to VEGF observed in ß₃-null endothelial cells and aortic rings in vitro. These data confirm that VEGF signaling via Flk1 is enhanced in ß₃-integrin–deficient mice and suggests that this increase may mediate the enhanced angiogenesis and tumor growth observed in these mice in vivo.

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