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Enhanced pathological angiogenesis in mice lacking β3 integrin or β3 and β5 integrins

Abstract

Inhibition of αvβ3 or αvβ5 integrin function has been reported to suppress neovascularization and tumor growth, suggesting that these integrins are critical modulators of angiogenesis. Here we report that mice lacking β3 integrins or both β3 and β5 integrins not only support tumorigenesis, but have enhanced tumor growth as well. Moreover, the tumors in these integrin-deficient mice display enhanced angiogenesis, strongly suggesting that neither β3 nor β5 integrins are essential for neovascularization. We also observed that angiogenic responses to hypoxia and vascular endothelial growth factor (VEGF) are augmented significantly in the absence of β3 integrins. We found no evidence that the expression or functions of other integrins were altered as a consequence of the β3 deficiency, but we did observe elevated levels of VEGF receptor-2 (also called Flk-1) in β3-null endothelial cells. These data indicate that αvβ3 and αvβ5 integrins are not essential for vascular development or pathological angiogenesis and highlight the need for further evaluation of the mechanisms of action of αv-integrin antagonists in anti-angiogenic therapeutics.

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Figure 1: Tumor growth and angiogenesis are enhanced in β3-deficient mice.
Figure 2: β35-null mice show enhanced tumor growth and angiogenesis.
Figure 3: β3 deficiency does not affect the expression or function of other integrins.
Figure 4: Hypoxia-induced retinal angiogenesis is enhanced in β3-null mice.
Figure 5: β3 deficiency enhances VEGF-induced vessel growth in vivo and in vitro.
Figure 6: Enhanced VEGFR-2 expression on β3-null endothelial cells.

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Acknowledgements

We thank B. Coller, E. Ruoslahti and L. Reichardt for antibodies against mouse β3-, αv and β5 integrin antibodies, respectively; G. Saunders, S. Watling and C. Wren for their technical assistance; G. Elias and colleagues for help with histology; J. Marshall for his gift of human β3-construct; F. Parkinson for her help in preparing the manuscript; and I. Hart for criticism during this study. This work was supported in part by grants from the NIH (PO1HL41484, PO1HL66105 and RO1CA17007 to R.O.H. and R01 HL64353, RO1 HL53949 to D.S.), and by the Howard Hughes Medical Institute. R.O.H. is an investigator and D.T. is an Associate of the Howard Hughes Medical Institute.

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Correspondence to Kairbaan M. Hodivala-Dilke.

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Reynolds, L., Wyder, L., Lively, J. et al. Enhanced pathological angiogenesis in mice lacking β3 integrin or β3 and β5 integrins. Nat Med 8, 27–34 (2002). https://doi.org/10.1038/nm0102-27

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