Skip to main content

Advertisement

Log in

Integrins in angiogenesis: multitalented molecules in a balancing act

  • Review
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Over the last 10–15 years the varied roles of cell adhesion molecules in the development of new blood vessels have received extensive attention. To date, more than 500 publications have been dedicated specifically to the role of a single family of adhesion molecules, namely integrins, in the process of angiogenesis. Although one can now appreciate the involvement of integrins in this process, and indeed antagonists of integrins are presently being tested as anti-angiogenic treatments, the precise regulation and exact action of integrins is still unclear. Here we will clarify the varied role of integrins and aim to elucidate and simplify the combined functions of these molecules in angiogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.

Similar content being viewed by others

References

  • Adams JC (2001) Thrombospondins: multifunctional regulators of cell interactions. Annu Rev Cell Dev Biol 17:25–51

    Article  CAS  PubMed  Google Scholar 

  • Albelda SM, Daise M, Levine EM, Buck CA (1989) Identification and characterization of cell-substratum adhesion receptors on cultured human-endothelial cells. J Clin Invest 83:1992–2002

    CAS  PubMed  Google Scholar 

  • Aoka Y, Johnson FL, Penta K, Hirata K, Hidai C, Schatzman R, Varner JA, Quertermous T (2002) The embryonic angiogenic factor Del1 accelerates tumor growth by enhancing vascular formation. Microvasc Res 64:148–161

    Article  CAS  PubMed  Google Scholar 

  • Babic AM, Kireeva ML, Kolesnikova TV, Lau LF (1998) CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth. Proc Natl Acad Sci U S A 95:6355–6360

    Article  CAS  PubMed  Google Scholar 

  • Babic AM, Chen CC, Lau LF (1999) Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin alpha(v)beta(3), promotes endothelial cell survival, and induces angiogenesis in vivo. Mol Cell Biol 19:2958–2966

    CAS  Google Scholar 

  • Bader BL, Rayburn H, Crowley D, Hynes RO (1998) Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all αv integrins. Cell 95:507–519

    CAS  PubMed  Google Scholar 

  • Bafetti LM, Young TN, Itoh Y, Stack MS (1998) Intact vitronectin induces matrix metalloproteinase-2 and tissue inhibitor of metalloproteinases-2 expression and enhanced cellular invasion by melanoma cells. J Biol Chem 273:143–149

    Article  CAS  PubMed  Google Scholar 

  • Baker AH, Edwards DR, Murphy G (2002) Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci 115:3719–3727

    Article  CAS  PubMed  Google Scholar 

  • Bellahcene A, Bonjean K, Fohr B, Fedarko NS, Robey FA, Young MF, Fisher LW, Castronovo V (2000) Bone sialoprotein mediates human endothelial cell attachment and migration and promotes angiogenesis. Circ Res 86:885–891

    CAS  PubMed  Google Scholar 

  • Bloch W, Forsberg E, Lentini S, Brakebusch C, Martin K, Krell HW, Weidle UH, Addicks K, Fassler R (1997) beta 1 integrin is essential for teratoma growth and angiogenesis. J Cell Biol 139:265–278

    Article  CAS  PubMed  Google Scholar 

  • Blystone SD, Graham IL, Lindberg FP, Brown EJ (1994) Integrin αvβ3 differentially regulates adhesive and phagocytic functions of the fibronectin receptor α5β1. J Cell Biol 127:11129–11137

    Google Scholar 

  • Brooks PC, Montgomery AMP, Rosenfeld M, Reisfeld RA, Hu T, Klier G, Cheresh DA (1994) Integrin αvβ3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79:1157–1164

    CAS  PubMed  Google Scholar 

  • Brooks PC, Stromblad S, Klemke R, Visscher D, Sarkar FH, Cheresh DA (1995) Antiintegrin αvβ3 blocks human breast cancer growth and angiogenesis in human skin. J Clin Invest 96:1815–1822

    CAS  PubMed  Google Scholar 

  • Brooks PC, Silletti S, von Schalscha TL, Friedlander M, Cheresh DA (1998) Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity. Cell 92:391–400

    CAS  PubMed  Google Scholar 

  • Buckley CD, Pilling D, Henriquez NV, Parsonage G, Threlfall K, Scheel-Toellner D, Simmons DL, Albar AN, Lord JM, Salmon M (1999) RGD peptides induce apoptosis by direct caspase-3 activation. Nature 397:534–539

    Article  CAS  PubMed  Google Scholar 

  • Burke PA, DeNardo SJ, Miers LA, Lamborn KR, Matzku S, DeNardo GL (2002) Cilengitide targeting of alpha(v)beta(3) integrin receptor synergizes with radioimmunotherapy to increase efficacy and apoptosis in breast cancer xenografts. Cancer Res 62:4263–4272

    CAS  PubMed  Google Scholar 

  • Byzova TV, Plow EF (1998) Activation of αvβ3 on vascular cells controls recognition of prothrombin. J Cell Biol 143:2081–2092

    Article  CAS  PubMed  Google Scholar 

  • Byzova TV, Goldman CK, Pampori N, KA T, Bett A, Shattil SJ, Plow EF (2000) A mechanism for modulation of cellular responses to VEGF: activation of the integrins. Mol Cell 6:851–860

    CAS  PubMed  Google Scholar 

  • Camenisch G, Pisabarro MT, Sherman D, Kowalski J, Nagel M, Hass P, Xie MH, Gurney A, Bodary S, Liang XH, Clark K, Beresini M, Ferrara N, Gerber HP (2002) ANGPTL3 stimulates endothelial cell adhesion and migration via integrin alpha(v)beta(3) and induces blood vessel formation in vivo. J Biol Chem 277:17281–17290

    Article  CAS  PubMed  Google Scholar 

  • Carlson TR, Feng YZ, Maisonpierre PC, Mrksich M, Morla AO (2001) Direct cell adhesion to the angiopoietins mediated by integrins. J Biol Chem 276:26516–26525

    Article  CAS  PubMed  Google Scholar 

  • Carmeliet P (2002) Integrin indecision. Nat Med. 8:14–16

    Google Scholar 

  • Chen JC, Diacovo TG, Grenache DG, Santoro SA, Zutter MM (2002) The alpha(2) integrin subunit-deficient mouse—a multifaceted phenotype including defects of branching morphogenesis and hemostasis. Am J Pathol 161:337–344

    CAS  PubMed  Google Scholar 

  • Cheresh DA, Stupack DG (2002) Integrin-mediated death: an explanation of the integrin-knockout phenotype? Nat Med 8:193–194

    Article  CAS  PubMed  Google Scholar 

  • Clark EA, Brugge JS (1995) Integrins and signal transduction pathways: the road taken. Science 268:233–239

    CAS  PubMed  Google Scholar 

  • Collo G, Pepper MS (1999) Endothelial cell integrin alpha 5 beta 1 expression is modulated by cytokines and during migration in vitro. J Cell Sci 112:569–578

    PubMed  Google Scholar 

  • Dechantsreiter MA, Planker E, Matha B, Lohof E, Holzemann G, Jonczyk A, Goodman SL, Kessler H (1999) N-methylated cyclic RGD peptides as highly active and selective alpha(v)beta(3) integrin antagonists. J Med Chem 42:3033–3040

    Article  CAS  PubMed  Google Scholar 

  • Deroanne C, Vouret-Craviari V, Pouysségur J (2003) EphrinA1 inactivates integrin-mediated vascular smooth muscle cell spreading via the Rac/PAK pathway. J Cell Sci 116:1367–1376

    Article  CAS  PubMed  Google Scholar 

  • Diaz-Gonzalez F, Forsyth J, Steiner B, Ginsberg MH (1996) Trans-dominant inhibition of integrin function. Mol Biol Cell 7:1939–1951

    CAS  PubMed  Google Scholar 

  • DiPersio CM, Hodivala-Dilke KM, Jaenisch R, Kreidberg JA, Hynes RO (1997) α3β1 integrin is required for normal development of the epidermal basement membrane. J Cell Biol 137:729–742

    Article  CAS  PubMed  Google Scholar 

  • DiPersio CM, van der Neut R, Georges-Labouesse E, Kreidberg JA, Sonnenberg A, Hynes RO (2000) alpha 3 beta 1 and alpha 6 beta 4 integrin receptors for laminin-5 are not essential for epidermal morphogenesis and homeostasis during skin development. J Cell Sci 113:3051–3062

    CAS  PubMed  Google Scholar 

  • Dormond O, Foletti A, Paroz C, Ruegg C (2001) NSAIDs inhibit alpha V beta 3 integrin-mediated and Cdc42/Rac-dependent endothelial-cell spreading, migration and angiogenesis. Nat Med 7:1041–1047

    Article  CAS  PubMed  Google Scholar 

  • Dowling J, Yu QC, Fuchs E (1996) beta 4 integrin is required for hemidesmosome formation, cell adhesion and cell survival. J Cell Biol 134:559–572

    CAS  PubMed  Google Scholar 

  • Drake CJ, Cheresh DA, Little CD (1995) An antagonist of integrin αvβ3 prevents maturation of blood vessels during embryonic neovascularization. J Cell Sci 108:2655–2661

    CAS  PubMed  Google Scholar 

  • Eliceiri BP, Cheresh DA (1999) The role of αv integrins during angiogenesis: insights into potential mechanisms of action and clinical development. J Clin Invest 103:1227–1230

    PubMed  Google Scholar 

  • Eliceiri BP, Paul R, Schwartzberg PL, Hood JD, Leng J, Cheresh DA (1999) Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol Cell 4:915–924

    PubMed  Google Scholar 

  • Enenstein J, Kramer RH (1994) Confocal microscopic analysis of integrin expression on the microvasculature and its sprouts in the neonatal foreskin. J Invest Dermatol 103:381–386

    CAS  PubMed  Google Scholar 

  • Fassler R, Pfaff M, Murphy J, Noegel AA, Johansson S, Timpl R, Albrecht R (1995) Lack of b1 integrin gene in embryonic stem cells affects morphology, adhesion, and migration but not integration into the inner cell mass of blastocysts. J Cell Biol 128:979–988

    PubMed  Google Scholar 

  • Francis SE, Goh KL, Hodivala-Dilke K, Bader BL, Stark M, Davidson D, Hynes RO (2002) Central roles of alpha(5)beta(1) integrin and fibronectin in vascular development in mouse embryos and embryoid bodies. Arterioscler Thromb Vasc Biol 22:927–933

    Article  CAS  PubMed  Google Scholar 

  • Friedlander M, Brooks PC, Shaffer RW, Kincaid CM, Varner JA, Cheresh DA (1995) Definition of two angiogenic pathways by distinct αv integrins. Science 270:1500–1502

    PubMed  Google Scholar 

  • Friedlander M, Theesfeld CL, Sugita M, Fruttiger M, Thomas MA, Chang S, Cheresh DA (1996) Involvement of integrins αvβ3 and αvβ5 in ocular neovascular diseases. Proc Natl Acad Sci U S A 93:9764–9769

    Article  CAS  PubMed  Google Scholar 

  • Frisch SM, Francis H (1994) Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 124:619–626

    CAS  PubMed  Google Scholar 

  • Fujiwara H, Kikkawa Y, Sanzen N, Sekiguchi K (2001) Purification and characterization of human laminin-8—laminin-8 stimulates cell adhesion and migration through alpha(3)beta(1) and alpha(6)beta(1) integrins. J Biol Chem 276:17550–17558

    Article  CAS  PubMed  Google Scholar 

  • Funahashi Y, Sugi NH, Semba T, Yamamoto Y, Hamaoka S, Tsukahara-Tamai N, Ozawa Y, Tsuruoka A, Nara K, Takahashi K, Okabe T, Kamata J, Owa T, Ueda N, Haneda T, Yonaga M, Yoshimatsu K, Wakabayashi T (2002) Sulfonamide derivative, E7820, is a unique angiogenesis inhibitor suppressing an expression of integrin alpha 2 subunit on endothelium. Cancer Res 62:6116–6123

    CAS  PubMed  Google Scholar 

  • Gao BC, Saba TM, Tsan MF (2002) Role of alpha(v)beta(3)-integrin in TNF-alpha-induced endothelial cell migration. Am J Physiol Cell Physiol 283:C1196–C1205

    CAS  PubMed  Google Scholar 

  • Gardner H, Kreidberg J, Koteliansky V, Jaenisch R (1996) Deletion of integrin alpha 1 by homologous recombination permits normal murine development but gives rise to a specific deficit in cell adhesion. Dev Biol 175:301–313

    Article  CAS  PubMed  Google Scholar 

  • George EL, GeorgesLabouesse EN, Patelking RS, Rayburn H, Hynes RO (1993) Defects in mesoderm, neural-tube and vascular development in mouse embryos lacking fibronectin. Development 119:1079–1091

    CAS  PubMed  Google Scholar 

  • George EL, Baldwin HS, Hynes RO (1997) Fibronectins are essential for heart and blood vessel morphogenesis but are dispensable for initial specification of precursor cells. Blood 90:3073–3081

    CAS  PubMed  Google Scholar 

  • GeorgesLabouesse E, Messaddeq N, Yehia G, Cadalbert L, Dierich A, LeMeur M (1996) Absence of integrin alpha 6 leads to epidermolysis bullosa and neonatal death in mice. Nat Genet 13:370–373

    CAS  PubMed  Google Scholar 

  • Giancotti FG (2000) Complexity and specificity of integrin signalling. Nat Cell Biol 2:E13–E14

    CAS  PubMed  Google Scholar 

  • Giancotti FG, Ruoslahti E (1999) Integrin signaling. Science 285:1028–1032

    Article  CAS  PubMed  Google Scholar 

  • Gingras D, Lamy S, Beliveau R (2000) Tyrosine phosphorylation of the vascular endothelial-growth-factor receptor-2 (VEGFR-2) is modulated by Rho proteins. Biochem J 348:273–280

    Article  CAS  PubMed  Google Scholar 

  • Goh KL, Yang JT, Hynes R (1997) Mesodermal defects and cranial neural crest apoptosis in alpha 5 integrin-null embryos. Development 124:4309–4319

    CAS  PubMed  Google Scholar 

  • Gonzalez AM, Gonzales M, Herron GS, Nagavarapu U, Hopkinson SB, Tsuruta D, Jones JCR (2002) Complex interactions between the laminin alpha 4 subunit and integrins regulate endothelial cell behavior in vitro and angiogenesis in vivo. Proc Natl Acad Sci U S A 99:16075–16080

    Article  CAS  PubMed  Google Scholar 

  • Grzeszkiewicz TM, Lindner V, Chen NY, Lam SCT, Lau LF (2002) The angiogenic factor cysteine-rich 61 (CYR61, CCN1) supports vascular smooth muscle cell adhesion and stimulates chemotaxis through integrin alpha(6)beta(1) and cell surface heparan sulfate proteoglycans. Endocrinology 143:1441–1450

    Google Scholar 

  • Gutheil JC, Campbell TN, Pierce PR, Watkins JD, Huse WD, Bodkin DJ, Cheresh DA (2000) Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3. Clin Cancer Res 6:3056–3061

    CAS  PubMed  Google Scholar 

  • Hammes H-P, Brownlee M, Jonczyk A, Sutter A, Preissner KT (1996) Subcutaneous injection of a cyclic peptide antagonist of vitronectin receptor-type integrins inhibits retinal neovascularization. Nat Med 2:529–533

    CAS  PubMed  Google Scholar 

  • Hidai C, Zupancic T, Penta K, Mikhail A, Kawana M, Quertermous EE, Aoka Y, Fukagawa M, Matsui Y, Platika D, Auerbach R, Hogan BLM, Snodgrass R, Quertermous T (1998) Cloning and characterization of developmental endothelial locus-1: an embryonic endothelial cell protein that binds the alpha v beta 3 integrin receptor. Genes Dev 12:21–33

    CAS  PubMed  Google Scholar 

  • Hodivala-Dilke KM, McHugh KP, Tsakiris DA, Rayburn H, Crowley D, Ullman-Cullere M, Ross FP, Coller BS, Teitelbaum S, Hynes RO (1999) Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest 103:229–238

    CAS  PubMed  Google Scholar 

  • Hood JD, Bednarski M, Frausto R, Guccione S, Reisfeld RA, Xiang R, Cheresh DA (2002) Tumor regression by targeted gene delivery to the neovasculature. Science 296:2404–2407

    Article  CAS  PubMed  Google Scholar 

  • Huang X, Griffiths M, Wu J, Farese RVJ, Sheppard D (2000) Normal development, wound healing, and adenovirus susceptibility in beta5-deficient mice. Mol Cell Biol 20:755–759

    Article  CAS  PubMed  Google Scholar 

  • Hughes SE (1996) Functional characterization of the spontaneously transformed human umbilical vein endothelial cell line ECV304: use in an in vitro model of angiogenesis. Exp Cell Res 225:171–185

    Article  CAS  PubMed  Google Scholar 

  • Hutchings H, Ortega N, Plouet J (2003) Extracellular matrix bound vascular endothelial growth factor promotes endothelial cell adhesion, migration, and survival through integrin ligation. FASEB J (in press)

  • Hynes RO (1992) Integrins: versatility modulation and signaling in cell adhesion. Cell 69:11–25

    CAS  PubMed  Google Scholar 

  • Hynes RO (2002) A reevaluation of integrins as regulators of angiogenesis. Nat Med 8:918–921

    Article  CAS  PubMed  Google Scholar 

  • Ingber DE, Folkman J (1989) Mechanochemical switching between growth and differentiation during fibroblast growth factor-stimulated angiogenesis in vitro: role of extracellular matrix. J Cell Biol 109:317–330

    CAS  PubMed  Google Scholar 

  • Jiang C, Jiang W, Ip C, Ganther H, Lu J (1999) Selenium-induced inhibition of angiogenesis in mammary cancer at chemopreventive levels of intake. Mol Carcinog 26:213–215

    CAS  PubMed  Google Scholar 

  • Jimenez B, Volpert OV, Crawford SE, Febbraio M, Silverstein RL, Bouck N (2000) Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat Med 6:41–48

    PubMed  Google Scholar 

  • Kanda S, Tomasini-Johansson B, Klint P, Dixelius J, Rubin K, Claesson-Welsh L (1999) Signaling via fibroblast growth factor receptor-1 is dependent on extracellular matrix in capillary endothelial cell differentiation. Exp Cell Res 248:203–213

    CAS  PubMed  Google Scholar 

  • Kang IC, Lee YD, Kim DS (1999) A novel disintegrin salmosin inhibits tumor angiogenesis. Cancer Res 59:3754–3760

    CAS  PubMed  Google Scholar 

  • Kanno S, Oda N, Abe M, Terai Y, Ito M, Shitara K, Tabayashi K, Shibuya M, Sato Y (2000) Roles of two VEGF receptors, Flt-1 and KDR, in the signal transduction of VEGF effects in human vascular endothelial cells. Oncogene 19:2138–2146

    Article  CAS  PubMed  Google Scholar 

  • Kim S, Harris M, Varner JA (2000a) Regulation of integrin avb3-mediated endothelial cell migration and angiogenesis by integrin a5b1 and protein kinase A. J Biol Chem 275:33920–33298

    Article  CAS  PubMed  Google Scholar 

  • Kim S, Bell K, Mousa SA, Varner JA (2000b) Regulation of angiogenesis in vivo by ligation of integrin α5β1 with the central cell-binding domain of fibronectin. Am J Pathol 156:1345–1362

    CAS  PubMed  Google Scholar 

  • Kim S, Bakre M, Yin H, Varner JA (2002a) Inhibition of endothelial cell survival and angiogenesis by protein kinase A. J Clin Invest 110:933–941

    Article  CAS  PubMed  Google Scholar 

  • Kim YM, Lee YM, Kim HS, Kim JD, Choi Y, Kim KW, Lee SY, Kwon YG (2002b) TNF-related activation-induced cytokine (TRANCE) induces angiogenesis through the activation of Src and phospholipase C (PLC) in human endothelial cells. J Biol Chem 277:6799–6805

    Article  CAS  PubMed  Google Scholar 

  • Kiosses WB, Hood J, Yang SY, Gerritsen ME, Cheresh DA, Alderson N, Schwartz MA (2002) A dominant-negative p65 PAK peptide inhibits angiogenesis. Circ Res 90:697–702

    Article  CAS  PubMed  Google Scholar 

  • Korff T, Augustin HG (1999) Tensional forces in fibrillar extracellular matrices control directional capillary sprouting. J Cell Sci 112:3249–3258

    CAS  PubMed  Google Scholar 

  • Kreidberg JA, Donovan MJ, Goldstein SL, Rennke H, Shepherd K, Jones RC, Jaenisch R (1996) Alpha 3 beta 1 integrin has a crucial role in kidney and lung organogenesis. Development 122:3537–3547

    CAS  PubMed  Google Scholar 

  • Kroon ME, Koolwijk P, van der Vecht B, van Hinsbergh VW (2000) Urokinase receptor expression on human microvascular endothelial cells is increased by hypoxia: implications for capillary-like tube formation in a fibrin matrix. Blood 96:2775–2783

    CAS  PubMed  Google Scholar 

  • Kumar CC, Armstrong L, Yin Z, Malkowski M, Maxwell E, Ling H, Yaremko B, Liu M, Varner J, Smith EM, Neustadt B, Nechuta T (2000) Targeting integrins alpha(v)beta(3) and alpha(v)beta(5) for blocking tumor-induced angiogenesis. In: Angiogenesis: from the molecular to integrative pharmacology. pp 169–180

  • Kumar CC, Malkowski M, Yin ZZ, Tanghetti E, Yaremko B, Nechuta T, Varner J, Liu M, Smith EM, Neustadt B, Presta M, Armstrong L (2001) Inhibition of angiogenesis and tumor growth by SCH221153, a dual alpha(v)beta(3) and alpha(v)beta(5) integrin receptor antagonist. Cancer Res 61:2232–2238

    CAS  PubMed  Google Scholar 

  • Kyriakides TR, Zhu YH, Smith LT, Bain SD, Yang ZT, Lin MT, Danielson KG, Iozzo RV, LaMarca M, McKinney CE, Ginns EI, Bornstein P (1998) Mice that lack thrombospondin 2 display connective tissue abnormalities that are associated with disordered collagen fibrillogenesis, an increased vascular density, and a bleeding diathesis. J Cell Biol 140:419–430

    CAS  PubMed  Google Scholar 

  • Lafleur MA, Handsley MM, Knauper V, Murphy G, Edwards DR (2002) Endothelial tubulogenesis within fibrin gels specifically requires the activity of membrane-type-matrix metalloproteinases (MT-MMPs). J Cell Sci 115:3427–3438

    CAS  PubMed  Google Scholar 

  • Lawler J (2000) The functions of thrombospondin-1 and 2. Curr Opin Cell Biol 12:634–640

    Article  CAS  PubMed  Google Scholar 

  • Lawler J, Sunday M, Thibert V, Duquette M, George EL, Rayburn H, Hynes RO (1998) Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J Clin Invest 101:982–992

    CAS  PubMed  Google Scholar 

  • Legler DF, Wiedle G, Ross FP, Imhof BA (2001) Superactivation of integrin alpha v beta 3 by low antagonist concentrations. J Cell Sci 114:1545–1553

    CAS  PubMed  Google Scholar 

  • Leu SJ, Lam SCT, Lau LF (2002) Pro-angiogenic activities of CYR61 (CCN1) mediated through integrins alpha(v)beta(3) and alpha(6)beta(1) in human umbilical vein endothelial cells. J Biol Chem 277:46248–46255

    Article  CAS  PubMed  Google Scholar 

  • Li R, Mitra N, Gratowski H, Vilaire G, Litinov R, Nagasami C, Weisel JW, Lear JD, DeGrado WF, Bennett JS (2003) Activation of integrin α11bβ3 by modulation of transmembrane helix associations. Science 300:795–798

    Article  CAS  PubMed  Google Scholar 

  • Liddington RC, Ginsberg MH (2002) Integrin activation takes shape. J Cell Biol 158:833–839

    Article  CAS  PubMed  Google Scholar 

  • Lode HN, Moehler T, Xiang R, Jonczyk A, Gillies SD, Cheresh DA, Reisfeld RA (1999) Synergy between an antiangiogenic integrin alphav antagonist and an antibody-cytokine fusion protein eradicates spontaneous tumor metastases. Proc Natl Acad Sci U S A 96:1591–1596

    Article  CAS  PubMed  Google Scholar 

  • Maeshima Y, Colorado PC, Kalluri R (2000) Two RGD-independent alpha vbeta 3 integrin binding sites on tumstatin regulate distinct anti-tumor properties. J Biol Chem 275:23745–23750

    Article  CAS  PubMed  Google Scholar 

  • Maeshima Y, Yerramalla UL, Dhanabal M, Holthaus KA, Barbashov S, Kharbanda S, Reimer C, Manfredi M, Dickerson WM, Kalluri R (2001) Extracellular matrix-derived peptide binds to alpha(v)beta(3) integrin and inhibits angiogenesis. J Biol Chem 276:31959–31968

    Article  CAS  PubMed  Google Scholar 

  • Maeshima Y, Sudhakar A, Lively JC, Ueki K, Kharbanda S, Kahn CR, Sonenberg N, Hynes RO, Kalluri R (2002) Tumstatin, an endothelial cell-specific inhibitor of protein synthesis. Science 295:140–143

    Article  CAS  PubMed  Google Scholar 

  • Marx M, Warren SL, Madri JA (2001) pp60(c-src) modulates microvascular endothelial phenotype and in vitro angiogenesis. Exp Mol Pathol 70:201–213

    Article  CAS  PubMed  Google Scholar 

  • Max R, Gerritsen RCM, Nooijen P, Goodman SL, Sutter A, Keilholz U, Ruiter DJ, DeWaal RMW (1997) Immunohistochemical analysis of integrin alpha v beta 3 expression on tumor associated vessels of human carcinomas—implications for anti-angiogenic treatment approaches. Eur J Cancer 33:208–208

    Article  Google Scholar 

  • Miranti CK, Brugge JS (2002) Sensing the environment: a historical perspective on integrin signal transduction. Nat Cell Biol 4:E83–E90

    Article  CAS  PubMed  Google Scholar 

  • Mitjans F, Meyer T, Fittschen C, Goodman S, Jonczyk A, Marshall JF, Reyes G, Piulats J (2000) In vivo therapy of malignant melanoma by means of antagonists of alpha v integrins. Int J Cancer 87:716–723

    Article  CAS  PubMed  Google Scholar 

  • Mo FE, Muntean AG, Chen CC, Stolz DB, Watkins SC, Lau LF (2002) CYR61 (CCN1) is essential for placental development and vascular integrity. Mol Cell Biol 22:8709–8720

    Article  CAS  PubMed  Google Scholar 

  • Oreilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao YH, Sage EH, Folkman J (1994) Angiostatin—a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung-carcinoma. Cell 79:315–328

    CAS  PubMed  Google Scholar 

  • Oreilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277–285

    PubMed  Google Scholar 

  • Paik JH, Chae SS, Lee MJ, Thangada S, Hla T (2001) Sphingosine 1-phosphate-induced endothelial cell migration requires the expression of EDG-1 and EDG-3 receptors and Rho-dependent activation of alpha(v)beta(3)- and beta(1)-containing integrins. J Biol Chem 276:11830–11837

    Article  CAS  PubMed  Google Scholar 

  • Pan LH, Beppu T, Kurose A, Yamauchi K, Sugawara A, Suzuki M, Ogawa A, Sawai T (2002) Neoplastic cells and proliferating endothelial cells express connective tissue growth factor (CTGF) in glioblastoma. Neurol Res 24:677–683

    CAS  PubMed  Google Scholar 

  • Pozzi A, Moberg PE, Miles LA, Wagner S, Soloway P, Gardner HA (2000) Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization. Proc Natl Acad Sci U S A 97:2202–2207

    Article  CAS  PubMed  Google Scholar 

  • Qi JH, Claesson-Welsh L (2001) VEGF-induced activation of phosphoinositide 3-kinase is dependent on focal adhesion kinase. Exp Cell Res 263:173–182

    Article  CAS  PubMed  Google Scholar 

  • Rehn M, Veikkola T, Kukk-Valdre E, Nakamura H, Ilmonen M, Lombardo CR, Pihlajaniemi T, Alitalo K, Vuori K (2001) Interaction of endostatin with integrins implicated in angiogenesis. PNAS 98:1024–1029

    Article  CAS  PubMed  Google Scholar 

  • Reynolds LE, Wyder L, Lively JC, Taverna D, Robinson SD, Huang X, Sheppard D, Hynes RO, Hodivala-Dilke KM (2002) Enhanced pathological angiogenesis in mice lacking beta3 integrin or beta3 and beta5 integrins. Nat Med 8:27–34

    Article  CAS  PubMed  Google Scholar 

  • Reynolds AR, Moghimi SM, Hodivala-Dilke K (2003) Nanoparticle-mediated gene delivery to tumour neovasculature. Trends Mol Med 9:2–4

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez-Manzaneque JC, Lane TF, Ortega MA, Hynes RO, Lawler J, Iruela-Arispe ML (2001) Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc Natl Acad Sci U S A 98:12485–12490

    Article  CAS  PubMed  Google Scholar 

  • Rusnati M, Tanghetti E, DellEra P, Gualandris A, Presta M (1997) alpha(v)beta(3) integrin mediates the cell-adhesive capacity and biological activity of basic fibroblast growth factor (FGF-2) in cultured endothelial cells. Mol Biol Cell 8:2449–2461

    CAS  PubMed  Google Scholar 

  • Schlessinger J (2000) New roles for Src kinases in control of cell survival and angiogenesis. Cell 100:293–296

    CAS  PubMed  Google Scholar 

  • Schneller M, Vuori K, Ruoslahti E (1997) alpha v beta 3 integrin associates with activated insulin and PDGF beta receptors and potentiates the biological activity of PDGF. EMBO J 16:5600–5607

    Article  CAS  PubMed  Google Scholar 

  • Schwartz MA, Ginsberg MH (2002) Networks and crosstalk: integrin signalling spreads. Nat Cell Biol 4:E65–E68

    CAS  PubMed  Google Scholar 

  • Senger DR, Claffey KP, Benes JE, Perruzzi CA, Sergiou AP, Detmar M (1997) Angiogenesis promoted by vascular endothelial growth factor: regulation through alpha1beta1 and alpha2beta1 integrins. Proc Natl Acad Sci U S A 94:13612–13617

    CAS  PubMed  Google Scholar 

  • Senger DR, Perruzzi CA, Streit M, Koteliansky VE, de Fougerolles AR, Detmar M (2002) 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. Am J Pathol 160:195–204

    CAS  PubMed  Google Scholar 

  • Sepp NT, Li L-J, Lee KH, Brown EJ, Caughman SW, Lawley TJ, Swerlick RA (1994) Basic fibroblast growth factor increases expression of the αvβ3 integrin complex on human microvascular endothelial cells. J Invest Dermatol 103:295–299

    CAS  PubMed  Google Scholar 

  • Sheppard D (2002) Endothelial integrins and angiogenesis: not so simple anymore. J Clin Invest 110:913–914

    Article  CAS  PubMed  Google Scholar 

  • Shin EY, Lee JY, Park MK, Chin YH, Jeong GB, Kim SY, Kim SR, Kim EG (1999) Overexpressed alpha(3)beta(1) and constitutively activated extracellular signal-regulated kinase modulate the angiogenic properties of ECV304 cells. Mol Cells 9:138–145

    CAS  PubMed  Google Scholar 

  • Shono T, Mochizuki Y, Kanetake H, Kanda S (2001) Inhibition of FGF-2-mediated chemotaxis of murine brain capillary endothelial cells by cyclic RGDfV peptide through blocking the redistribution of c-Src into focal adhesions. Exp Cell Res 268:169–178

    Article  CAS  PubMed  Google Scholar 

  • Silletti S, Kessler T, Goldberg J, Boger DL, Cheresh DA (2001) Disruption of matrix metalloproteinase 2 binding to integrin alpha vbeta 3 by an organic molecule inhibits angiogenesis and tumor growth in vivo. Proc Natl Acad Sci U S A 98:119–124

    CAS  PubMed  Google Scholar 

  • Smyth SS, Patterson C (2002) Tiny dancers: the integrin-growth factor nexus in angiogenic signaling. J Cell Biol 158:17–21

    Article  CAS  PubMed  Google Scholar 

  • Soga N, Namba N, McAllister S, Cornelius L, Teitelbaum SL, Dowdy SF, Kawamura J, Hruska KA (2001) Rho family GTPases regulate VEGF-stimulated endothelial cell motility. Exp Cell Res 269:73–87

    Article  CAS  PubMed  Google Scholar 

  • Soldi R, Mitola S, Strasly M, Defilippi P, Tarone G, Bussolino F (1999) Role of αvβ3 integrin in the activation of vascular endothelial growth factor receptor-2. EMBO J 18:882–892

    CAS  Google Scholar 

  • Stephens LE, Sutherland AE, Klimanskaya IV, Andrieux A, Meneses J, Pedersen RA, Damsky CH (1995) Deletion of beta-1 integrins in mice results in inner cell mass failure and periimplantation lethality. Genes Dev 9:1883–1895

    CAS  PubMed  Google Scholar 

  • Stoeltzing O, Liu WB, Reinmuth N, Fan F, Parry GC, Parikh AA, McCarty MF, Bucana CD, Mazar AP, Ellis LM (2003) Inhibition of integrin alpha(5)beta(1) function with a small peptide (ATN-161) plus continuous 5-FU infusion reduces colorectal liver metastases and improves survival in mice. Int J Cancer 104:496–503

    Article  CAS  PubMed  Google Scholar 

  • Storgard CM, Stupack DG, Jonczyk A, Goodman SL, Fox RI, Cheresh DA (1999) Decreased angiogenesis and arthritic disease in rabbits treated with an αvβ3 antagonist. J Clin Invest

  • Stupack DG, Cheresh DA (2002) ECM remodelling regulates angiogenesis: endothelial integrins look for new ligands. Science's STKE 2002:PE7

  • Stupack DG, Puente XS, Boutsaboualoy S, Storgard CM, Cheresh DA (2001) Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins. J Cell Biol 155:459–470

    Article  CAS  PubMed  Google Scholar 

  • Sudhakar A, Sugimoto H, Yang C, Lively J, Zeisberg M, Kalluri R (2003) Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by αvβ3 and α5β1 integrins. Proc Natl Acad Sci U S A 100:4766–4771

    Article  CAS  PubMed  Google Scholar 

  • Tanghetti E, Ria R, Dell'Era P, Urbinati C, Rusnati M, Ennas MG, Presta M (2002) Biological activity of substrate-bound basic fibroblast growth factor (FGF2): recruitment of FGF receptor-1 in endothelial cell adhesion contacts. Oncogene 21:3889–3897

    Article  CAS  PubMed  Google Scholar 

  • Tarui T, Miles LA, Takada Y (2001) Specific interaction of angiostatin with integrin alpha(v)beta(3) in endothelial cells. J Biol Chem 276:39562–39568

    Article  CAS  PubMed  Google Scholar 

  • Taverna D, Hynes RO (2001) Reduced blood vessel formation and tumor growth in alpha5-integrin-negative teratocarcinomas and embryoid bodies. Cancer Res 61:5255–5261

    CAS  PubMed  Google Scholar 

  • Tucker GC (2002) Inhibitors of integrins. Curr Opin Pharmacol 2:394–402

    Article  CAS  PubMed  Google Scholar 

  • van der Flier A, Sonnenberg A (2001) Function and interactions of integrins. Cell Tissue Res 305:285–298

    PubMed  Google Scholar 

  • van der Neut R, Krimpenfort P, Calafat J, Niessen CM, Sonnenberg A (1996) Epithelial detachment due to absence of hemidesmosomes in integrin beta 4 null mice. Nat Genet 13:366–369

    CAS  PubMed  Google Scholar 

  • Varner KA, Cheresh DA (1996) Integrins and cancer. Curr Opin Cell Biol 8:724–730

    CAS  PubMed  Google Scholar 

  • Whelan MC, Senger DR (2003) Collagen I initiates endothelial cell morphogenesis by inducing actin polymerization through suppression of cyclic AMP and protein kinase A. J Biol Chem 278:327–334

    Article  CAS  PubMed  Google Scholar 

  • Xiong JP, Stehle T, Diefenbach B, Zhang R, Dunker R, Scott DL, Joachimiak A, Goodman SL, Arnaout MA (2001) Crystal structure of the extracellular segment of integrin alpha v beta3. Science 294:339–345

    Article  CAS  PubMed  Google Scholar 

  • Xiong JP, Stehle T, Zhang RG, Joachimiak A, Frech M, Goodman SL, Aranout MA (2002) Crystal structure of the extracellular segment of integrin alpha v beta 3 in complex with an Arg-Gly-Asp ligand. Science 296:151–155

    Google Scholar 

  • Xu JS, Rodriguez D, Petitclerc E, Kim JJ, Hangai M, Moon YS, Davis GE, Brooks PC (2001) Proteolytic exposure of a cryptic site within collagen type IV is required for angiogenesis and tumor growth in vivo (vol 154, p 1069, 2001). J Cell Biol 155:859–859

    Article  CAS  Google Scholar 

  • Yamada KM, Even-Ram S (2002) Integrin regulation of growth factor receptors. Nat Cell Biol 4:E75–E76

    Article  CAS  PubMed  Google Scholar 

  • Yang JT, Rayburn H, Hynes RO (1993) Embryonic mesodermal defects in alpha(5) integrin-deficient mice. Development 119:1093–1105

    CAS  PubMed  Google Scholar 

  • Yeh CH, Peng H-C, Huang T-F (1998) Accutin, a new disintegrin, inhibits angiogenesis in vitro and in vivo by acting as integrin αvβ3 antagonist and inducing apoptosis. Blood 9:3268–3276

    Google Scholar 

  • Yeh CH, Peng HC, Huang TF (1999) Cytokines modulate integrin alpha(v)beta(3)-mediated human endothelial cell adhesion and calcium signaling. Exp Cell Res 251:57–66

    Article  CAS  PubMed  Google Scholar 

  • Zhu J, Motejlek K, Wang D, Zang K, Schmidt A, Reichardt LF (2002) β8 integrins are required for vascular morphogenesis in mouse embryos. Development 129:2891–2903

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Fiona Parkinson for her invaluable help in preparing this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kairbaan M. Hodivala-Dilke.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hodivala-Dilke, K.M., Reynolds, A.R. & Reynolds, L.E. Integrins in angiogenesis: multitalented molecules in a balancing act. Cell Tissue Res 314, 131–144 (2003). https://doi.org/10.1007/s00441-003-0774-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-003-0774-5

Keywords

Navigation