Home LiteratureArticle Details
PMID: 11786413 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

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.

The American journal of pathology ·Vol. 160 ·No. 1 ·2002-01-00 ·Pages 195-204

Senger DR, Perruzzi CA, Streit M, Koteliansky VE, de Fougerolles AR, Detmar M

Abstract

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.

MeSH Terms
Animals Carcinoma, Squamous Cell/blood supply Cell Division/physiology Cell Movement/physiology Cells, Cultured Endothelial Growth Factors/physiology Endothelium, Vascular/cytology,physiology Female Humans Integrin alpha1beta1 Integrins/physiology Lymphokines/physiology Mice Mice, Inbred BALB C Microcirculation Neoplasm Transplantation Neovascularization, Pathologic/physiopathology Neovascularization, Physiologic/physiology Receptors, Collagen Signal Transduction/physiology Skin/blood supply Transplantation, Heterologous Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors
Chemicals
Endothelial Growth Factors Integrin alpha1beta1 Integrins Lymphokines Receptors, Collagen Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Senger Donald R
Department of Pathology, Beth Israel Deaconess Medical Center, Boston 02215, USA. dsenger@caregroup.harvard.edu
Perruzzi Carole A
Streit Michael
Koteliansky Victor E
de Fougerolles Antonin R
Detmar Michael
References (47)
47 references, click to expand
  1. Regulation of inflammation by collagen-binding integrins alpha1beta1 and alpha2beta1 in models of hypersensitivity and arthritis.
    J Clin Invest. 2000 Mar;105(6):721-9 PMID: 10727440
  2. A simple, quantitative method for assessing angiogenesis and antiangiogenic agents using reconstituted basement membrane, heparin, and fibroblast growth factor.
    Lab Invest. 1992 Oct;67(4):519-28 PMID: 1279270
  3. Thrombospondin-2: a potent endogenous inhibitor of tumor growth and angiogenesis.
    Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14888-93 PMID: 10611308
  4. Expression of vascular endothelial growth factor induces an invasive phenotype in human squamous cell carcinomas.
    Am J Pathol. 2000 Jan;156(1):159-67 PMID: 10623663
  5. Focal adhesion kinase mediates the integrin signaling requirement for growth factor activation of MAP kinase.
    J Cell Biol. 1999 Nov 1;147(3):611-8 PMID: 10545504
  6. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells.
    Biochem Biophys Res Commun. 1989 Jun 15;161(2):851-8 PMID: 2735925
  7. VLA-2 mediates the interaction of collagen with endothelium during in vitro vascular tube formation.
    Cell Biol Int. 1994 Sep;18(9):859-67 PMID: 7528076
  8. Vascular endothelial growth factor promotes tumor dissemination by a mechanism distinct from its effect on primary tumor growth.
    Cancer Res. 1996 Feb 15;56(4):921-4 PMID: 8631034
  9. Stimulation of endothelial cell migration by vascular permeability factor/vascular endothelial growth factor through cooperative mechanisms involving the alphavbeta3 integrin, osteopontin, and thrombin.
    Am J Pathol. 1996 Jul;149(1):293-305 PMID: 8686754
  10. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation.
    J Biol Chem. 1998 Nov 13;273(46):30336-43 PMID: 9804796
  11. The MAPK signaling cascade.
    FASEB J. 1995 Jun;9(9):726-35 PMID: 7601337
  12. Integrins.
    Kidney Int Suppl. 1994 Jan;44:S17-22 PMID: 8127030
  13. Angiogenesis promoted by vascular endothelial growth factor: regulation through alpha1beta1 and alpha2beta1 integrins.
    Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13612-7 PMID: 9391074
  14. Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor.
    Cancer Res. 1990 Mar 15;50(6):1774-8 PMID: 2155059
  15. Collagen and elastin of human dermis.
    J Invest Dermatol. 1960 Oct;35:227-9 PMID: 13783962
  16. Nitric oxide is an upstream signal of vascular endothelial growth factor-induced extracellular signal-regulated kinase1/2 activation in postcapillary endothelium.
    J Biol Chem. 1998 Feb 13;273(7):4220-6 PMID: 9461619
  17. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels.
    Cell. 1994 Dec 30;79(7):1157-64 PMID: 7528107
  18. Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity.
    Arch Ophthalmol. 1996 Oct;114(10):1219-28 PMID: 8859081
  19. Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins.
    Cell. 1998 Nov 13;95(4):507-19 PMID: 9827803
  20. Integrins, adhesion and apoptosis.
    Trends Cell Biol. 1997 Apr;7(4):146-50 PMID: 17708932
  21. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.
    Am J Pathol. 1995 May;146(5):1029-39 PMID: 7538264
  22. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid.
    Science. 1983 Feb 25;219(4587):983-5 PMID: 6823562
  23. Confluence of vascular endothelial cells induces cell cycle exit by inhibiting p42/p44 mitogen-activated protein kinase activity.
    Mol Cell Biol. 1999 Apr;19(4):2763-72 PMID: 10082542
  24. Vascular permeability factor (VPF, VEGF) in tumor biology.
    Cancer Metastasis Rev. 1993 Sep;12(3-4):303-24 PMID: 8281615
  25. Regulation of angiogenesis in vivo by ligation of integrin alpha5beta1 with the central cell-binding domain of fibronectin.
    Am J Pathol. 2000 Apr;156(4):1345-62 PMID: 10751360
  26. Trans-dominant inhibition of integrin function.
    Mol Biol Cell. 1996 Dec;7(12):1939-51 PMID: 8970156
  27. A mechanism for modulation of cellular responses to VEGF: activation of the integrins.
    Mol Cell. 2000 Oct;6(4):851-60 PMID: 11090623
  28. Integrin signaling.
    Science. 1999 Aug 13;285(5430):1028-32 PMID: 10446041
  29. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity.
    Nat Med. 1995 Oct;1(10):1024-8 PMID: 7489357
  30. Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis.
    Microvasc Res. 1977 Jul;14(1):53-65 PMID: 895546
  31. Glomerular epithelial and mesangial cells differentially modulate the binding specificities of VLA-1 and VLA-2.
    Lab Invest. 1995 Mar;72(3):367-75 PMID: 7898055
  32. Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization.
    Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2202-7 PMID: 10681423
  33. Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody.
    Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14765-70 PMID: 8962129
  34. Integrins: versatility, modulation, and signaling in cell adhesion.
    Cell. 1992 Apr 3;69(1):11-25 PMID: 1555235
  35. Regulation of anchorage-dependent signal transduction by protein kinase A and p21-activated kinase.
    Nat Cell Biol. 2000 Sep;2(9):593-600 PMID: 10980699
  36. Fibronectin receptor functions in embryonic cells deficient in alpha 5 beta 1 integrin can be replaced by alpha V integrins.
    Mol Biol Cell. 1996 Nov;7(11):1737-48 PMID: 8930896
  37. Growth factor activation of MAP kinase requires cell adhesion.
    EMBO J. 1997 Sep 15;16(18):5592-9 PMID: 9312018
  38. Targeted mutations in integrins and their ligands: their implications for vascular biology.
    Thromb Haemost. 1997 Jul;78(1):83-7 PMID: 9198133
  39. Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival.
    J Clin Invest. 1999 Jan;103(2):229-38 PMID: 9916135
  40. Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor.
    Nat Med. 1999 Dec;5(12):1390-5 PMID: 10581081
  41. Cell anchorage permits efficient signal transduction between ras and its downstream kinases.
    J Biol Chem. 1997 Apr 4;272(14):8849-52 PMID: 9082999
  42. An antagonist of integrin alpha v beta 3 prevents maturation of blood vessels during embryonic neovascularization.
    J Cell Sci. 1995 Jul;108 ( Pt 7):2655-61 PMID: 7593306
  43. Endothelial receptor tyrosine kinases involved in angiogenesis.
    J Cell Biol. 1995 May;129(4):895-8 PMID: 7538139
  44. Definition of two angiogenic pathways by distinct alpha v integrins.
    Science. 1995 Dec 1;270(5241):1500-2 PMID: 7491498
  45. The role of vascular endothelial growth factor in pathological angiogenesis.
    Breast Cancer Res Treat. 1995;36(2):127-37 PMID: 8534862
  46. Anchorage-dependent regulation of the mitogen-activated protein kinase cascade by growth factors is supported by a variety of integrin alpha chains.
    J Biol Chem. 1999 Oct 29;274(44):31223-8 PMID: 10531317
  47. An alpha 2 beta 1 integrin-dependent pinocytic mechanism involving intracellular vacuole formation and coalescence regulates capillary lumen and tube formation in three-dimensional collagen matrix.
    Exp Cell Res. 1996 Apr 10;224(1):39-51 PMID: 8612690
Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.1016/s0002-9440(10)64363-5
Email
dsenger@caregroup.harvard.edu
Published
2002-01-00
Pages
195-204
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1867136
Subset
IM
Grants
NCI NIH HHS · CA86410 · United States
NCI NIH HHS · CA77357 · United States
NCI NIH HHS · R01 CA069184 · United States
NCI NIH HHS · R01 CA077357 · United States
NCI NIH HHS · CA69184 · United States
NCI NIH HHS · R01 CA086410 · United States
External Links
PubMed source DOI: 10.1016/s0002-9440(10)64363-5 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2