The α1β1 and α2β1 Integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis

被引:265
作者
Senger, DR
Perruzzi, CA
Streit, M
Koteliansky, VE
de Fougerolles, AR
Detmar, M
机构
[1] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA
[2] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA
[3] Massachusetts Gen Hosp, Dept Dermatol, Charlestown, MA USA
[4] Harvard Univ, Sch Med, Charlestown, MA USA
[5] Biogen Inc, Cambridge, MA 02142 USA
关键词
D O I
10.1016/S0002-9440(10)64363-5
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
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 alpha(1)beta(1) and alpha(2)beta(1) integrins support angiogenesis driven by vascular endothelial growth factor (VEGF). Dermal microvascular EC attachment through either alpha(1)beta(1) or alpha(2)beta(1) 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 alpha(1)beta(1) and alpha(2)beta(1) as was VEGF-stimulated chemotaxis of ECs in a uniform collagen matrix. Consistent with the functions of alpha(1)beta(1) and alpha(2)beta(1) 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 alpha(1)beta(1), and alpha(2)beta(1) substantially reduced tumor growth and angiogenesis of human squamous cell carcinoma xenografts. Collectively, these studies identify critical collaborative functions for the alpha(1)beta(1) and alpha(2)beta(1) integrins in supporting VEGF signal transduction, EC migration, and tumor angiogenesis.
引用
收藏
页码:195 / 204
页数:10
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