Involvement of αvβ3 integrin in gremlin-induced angiogenesis
Tóm tắt
αvβ3 integrin modulates pro-angiogenic endothelial cell (EC) responses following vascular endothelial growth factor receptor-2 (VEGFR2) engagement. The bone morphogenic protein antagonist gremlin is a novel non-canonical VEGFR2 ligand that promotes the acquisition of a pro-angiogenic phenotype in ECs. Here we investigated the role of αvβ3 and extracellular matrix components on EC activation induced by gremlin. Gremlin triggers VEGFR2 phosphorylation and cell motility in ECs adherent to the αvβ3 ligand fibrinogen but not in ECs adherent to type-I collagen or fibronectin. Also, gremlin and VEGF-A stimulate the formation of VEGFR2/αvβ3 integrin complexes as shown by co-immunoprecipitation experiments and fluorescence resonance energy transfer analysis of β3-ECFP/VEGFR2-EYFP co-transfected ECs. Accordingly, anti-β3 antibodies block the angiogenic activity exerted by gremlin or VEGF-A in vitro, ex vivo and in vivo. The results demonstrate a non-redundant role for αvβ3 in gremlin-induced angiogenesis and emphasize its contribution to the formation of functional multi-molecular VEGFR2 complexes responsible for the neovascularization events triggered by canonical and non-canonical pro-angiogenic VEGFR2 ligands.
Tài liệu tham khảo
Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257
Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1:27–31
Ferrara N (2010) Binding to the extracellular matrix and proteolytic processing: two key mechanisms regulating vascular endothelial growth factor action. Mol Biol Cell 21:687–690
Ingber DE, Folkman J (1987) Regulation of endothelial growth factor action: solid state control by extracellular matrix. Prog Clin Biol Res 249:273–282
Bussolino F, Serini G, Mitola S, Bazzoni G, Dejana E (2001) Dynamic modules and heterogeneity of function: a lesson from tyrosine kinase receptors in endothelial cells. EMBO Rep 2:763–767
Berger P, Ballmer-Hofer K (2011) The reception and the party after: how vascular endothelial growth factor receptor 2 explores cytoplasmic space. Swiss medical weekly 141:w13318
Soldi R, Mitola S, Strasly M, Defilippi P, Tarone G, Bussolino F (1999) Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2. The EMBO journal 18:882–892
Byzova TV, Goldman CK, Pampori N, Thomas KA, 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
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 journal: official publication of the Federation of American Societies for Experimental Biology 17:1520–1522
Robinson SD, Reynolds LE, Kostourou V, Reynolds AR, da Silva RG, Tavora B, Baker M, Marshall JF, Hodivala-Dilke KM (2009) Alphav beta3 integrin limits the contribution of neuropilin-1 to vascular endothelial growth factor-induced angiogenesis. The Journal of biological chemistry 284:33966–33981
Pearce JJ, Penny G, Rossant J (1999) A mouse cerberus/Dan-related gene family. Dev Biol 209:98–110
Vitt UA, Hsu SY, Hsueh AJ (2001) Evolution and classification of cystine knot-containing hormones and related extracellular signaling molecules. Mol Endocrinol 15:681–694
Balemans W, Van Hul W (2002) Extracellular regulation of BMP signaling in vertebrates: a cocktail of modulators. Dev Biol 250:231–250
Khokha MK, Hsu D, Brunet LJ, Dionne MS, Harland RM (2003) Gremlin is the BMP antagonist required for maintenance of Shh and Fgf signals during limb patterning. Nat Genet 34:303–307
Lu MM, Yang H, Zhang L, Shu W, Blair DG, Morrisey EE (2001) The bone morphogenic protein antagonist gremlin regulates proximal-distal patterning of the lung. Dev Dyn 222:667–680
Michos O, Panman L, Vintersten K, Beier K, Zeller R, Zuniga A (2004) Gremlin-mediated BMP antagonism induces the epithelial-mesenchymal feedback signaling controlling metanephric kidney and limb organogenesis. Development 131:3401–3410
Costello CM, Cahill E, Martin F, Gaine S, McLoughlin P (2009) Role of gremlin in the lung: development and disease. Am J Respir Cell Mol Biol 42:517–523
Lappin DW, McMahon R, Murphy M, Brady HR (2002) Gremlin: an example of the re-emergence of developmental programmes in diabetic nephropathy. Nephrol Dial Transplant 17(Suppl 9):65–67
Namkoong H, Shin SM, Kim HK, Ha SA, Cho GW, Hur SY, Kim TE, Kim JW (2006) The bone morphogenetic protein antagonist gremlin 1 is overexpressed in human cancers and interacts with YWHAH protein. BMC Cancer 6:74
Sneddon JB, Zhen HH, Montgomery K, van de Rijn M, Tward AD, West R, Gladstone H, Chang HY, Morganroth GS, Oro AE, Brown PO (2006) Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation. Proc Natl Acad Sci USA 103:14842–14847
Stabile H, Mitola S, Moroni E, Belleri M, Nicoli S, Coltrini D, Peri F, Pessi A, Orsatti L, Talamo F, Castronovo V, Waltregny D, Cotelli F, Ribatti D, Presta M (2007) Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor. Blood 109:1834–1840
Mitola S, Moroni E, Ravelli C, Andres G, Belleri M, Presta M (2008) Angiopoietin-1 mediates the pro-angiogenic activity of the bone morphogenic protein antagonist Drm. Blood 112:1154–1157
Mitola S, Ravelli C, Moroni E, Salvi V, Leali D, Ballmer-Hofer K, Zammataro L, Presta M (2010) Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2. Blood 116:3677–3680
Chiodelli P, Mitola S, Ravelli C, Oreste P, Rusnati M, Presta M (2011) Heparan sulfate proteoglycans mediate the angiogenic activity of the vascular endothelial growth factor receptor-2 agonist gremlin. Arterioscler Thromb Vasc Biol 31:e116–e127
Grinspan JB, Mueller SN, Levine EM (1983) Bovine endothelial cells transformed in vitro by benzo(a)pyrene. J Cell Physiol 114:328–338
Urbinati C, Ravelli C, Tanghetti E, Belleri M, Giacopuzzi E, Monti E, Presta M, Rusnati M (2012) Substrate-Immobilized HIV-1 Tat drives VEGFR2/alphavbeta3-integrin complex formation and polarization in endothelial cells. Arteriosclerosis, thrombosis, and vascular biology
Karpova TS, Baumann CT, He L, Wu X, Grammer A, Lipsky P, Hager GL, McNally JG (2003) Fluorescence resonance energy transfer from cyan to yellow fluorescent protein detected by acceptor photo bleaching using confocal microscopy and a single laser. J Microsc 209:56–70
Somanath PR, Malinin NL, Byzova TV (2009) Cooperation between integrin alphavbeta3 and VEGFR2 in angiogenesis. Angiogenesis 12:177–185
Mitola S, Brenchio B, Piccinini M, Tertoolen L, Zammataro L, Breier G, Rinaudo MT, den Hertog J, Arese M, Bussolino F (2006) Type I collagen limits VEGFR-2 signaling by a SHP2 protein-tyrosine phosphatase-dependent mechanism 1. Circ Res 98:45–54
Drake CJ, Cheresh DA, Little CD (1995) An antagonist of integrin alpha v beta 3 prevents maturation of blood vessels during embryonic neovascularization. J Cell Sci 108(Pt 7):2655–2661
Abdullah SE, Perez-Soler R (2011) Mechanisms of resistance to vascular endothelial growth factor blockade. Cancer
Weis SM, Cheresh DA (2011) Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17:1359–1370
Borges E, Jan Y, Ruoslahti E (2000) Platelet-derived growth factor receptor beta and vascular endothelial growth factor receptor 2 bind to the beta 3 integrin through its extracellular domain. The Journal of biological chemistry 275:39867–39873
West XZ, Meller N, Malinin NL, Deshmukh L, Meller J, Mahabeleshwar GH, Weber ME, Kerr BA, Vinogradova O, Byzova TV (2012) Integrin beta(3) Crosstalk with VEGFR Accommodating Tyrosine Phosphorylation as a Regulatory Switch. PLoS ONE 7:e31071
Brozzo MS, Bjelic S, Kisko K, Schleier T, Leppanen VM, Alitalo K, Winkler FK, Ballmer-Hofer K (2012) Thermodynamic and structural description of allosterically regulated VEGFR-2 dimerization. Blood 119:1781–1788