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1ß1 and 2ß1 Integrins Provide Critical Support for Vascular Endothelial Growth Factor Signaling, Endothelial Cell Migration, and Tumor Angiogenesis
From the Department of Pathology,*
Beth Israel Deaconess
Medical Center, Boston; the Cutaneous Biology Research Center and the
Department of Dermatology,
Massachusetts
General Hospital and Harvard Medical School, Charlestown; and Biogen,
Incorporated,
Cambridge, Massachusetts
Angiogenesis is a complex process, involving functional
cooperativity between cytokines and endothelial cell (EC) surface
integrins. In this study, we investigated the mechanisms
through which the 
1ß1 and
2ß1 integrins support angiogenesis driven
by vascular endothelial growth factor (VEGF). Dermal microvascular EC
attachment through either 1ß1 or
2ß1 supported robust VEGF activation of
the Erk1/Erk2 (p44/42) mitogen-activated protein kinase signal
transduction pathway that drives EC proliferation. Haptotactic EC
migration toward collagen I was dependent on
1ß1 and 2ß1
as was VEGF-stimulated chemotaxis of ECs in a uniform collagen matrix.
Consistent with the functions of 1ß1 and
2ß1 in supporting signal transduction and
EC migration, antibody antagonism of either integrin resulted
in potent inhibition of VEGF-driven angiogenesis in mouse skin.
Moreover, combined antagonism of
1ß1 and 2ß1
substantially reduced tumor growth and angiogenesis of human squamous
cell carcinoma xenografts. Collectively, these studies identify
critical collaborative functions for the
1ß1 and 2ß1
integrins in supporting VEGF signal transduction, EC
migration, and tumor angiogenesis.
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