The alpha(1)beta(1) and alpha(2)beta(1) integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis.
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.
Senger
Donald R
DR
Department of Pathology, Beth Israel Deaconess Medical Center, Boston 02215, USA. dsenger@caregroup.harvard.edu
Perruzzi
Carole A
CA
Streit
Michael
M
Koteliansky
Victor E
VE
de Fougerolles
Antonin R
AR
Detmar
Michael
M
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply*; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D005260:Female; D006801:Humans; D039222:Integrin alpha1beta1; D016023:Integrins / Q000502:physiology*; D008222:Lymphokines / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008833:Microcirculation; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000502:physiology; D038981:Receptors, Collagen; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000098:blood supply; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D039222:Integrin alpha1beta1; D016023:Integrins; D008222:Lymphokines; D038981:Receptors, Collagen; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors