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Angiogenesis

, Volume 19, Issue 3, pp 297–309 | Cite as

EphrinB2/EphB4 pathway in postnatal angiogenesis: a potential therapeutic target for ischemic cardiovascular disease

  • Du Yang
  • Chunna Jin
  • Hong Ma
  • Mingyuan Huang
  • Guo-Ping Shi
  • Jianan Wang
  • Meixiang Xiang
Review Paper

Abstract

Ischemic cardiovascular disease remains one of the leading causes of morbidity and mortality in the world. Proangiogenic therapy appears to be a promising and feasible strategy for the patients with ischemic cardiovascular disease, but the results of preclinical and clinical trials are limited due to the complicated mechanisms of angiogenesis. Facilitating the formation of functional vessels is important in rescuing the ischemic cardiomyocytes. EphrinB2/EphB4, a novel pathway in angiogenesis, plays a critical role in both microvascular growth and neovascular maturation. Hence, investigating the mechanisms of EphrinB2/EphB4 pathway in angiogenesis may contribute to the development of novel therapeutics for ischemic cardiovascular disease. Previous reviews mainly focused on the role of EphrinB2/EphB4 pathway in embryo vascular development, but their role in postnatal angiogenesis in ischemic heart disease has not been fully illustrated. Here, we summarized the current knowledge of EphrinB2/EphB4 in angiogenesis and their interaction with other angiogenic pathways in ischemic cardiovascular disease.

Keywords

Ischemic cardiovascular disease EphrinB2/EphB4 pathway Angiogenesis Vessel maturation VEGF-Dll4/Notch-EphrinB2 cascade 

Notes

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (Nos. 81270179 and 81470384 to M.X.X.).

Compliance with ethical standards

Conflict of interest

None declared.

References

  1. 1.
    Shah AM, Mann DL (2011) In search of new therapeutic targets and strategies for heart failure: recent advances in basic science. Lancet 378(9792):704–712. doi: 10.1016/S0140-6736(11)60894-5 PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Yellon DM, Hausenloy DJ (2007) Myocardial reperfusion injury. N Engl J Med 357(11):1121–1135. doi: 10.1056/NEJMra071667 PubMedCrossRefGoogle Scholar
  3. 3.
    van der Laan AM, Piek JJ, van Royen N (2009) Targeting angiogenesis to restore the microcirculation after reperfused MI. Nat Rev Cardiol 6(8):515–523. doi: 10.1038/nrcardio.2009.103 PubMedCrossRefGoogle Scholar
  4. 4.
    Lassaletta AD, Chu LM, Sellke FW (2011) Therapeutic neovascularization for coronary disease: current state and future prospects. Basic Res Cardiol 106(6):897–909. doi: 10.1007/s00395-011-0200-1 PubMedCrossRefGoogle Scholar
  5. 5.
    Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9(6):653–660. doi: 10.1038/nm0603-653 PubMedCrossRefGoogle Scholar
  6. 6.
    Risau W (1997) Mechanisms of angiogenesis. Nature 386(6626):671–674. doi: 10.1038/386671a0 PubMedCrossRefGoogle Scholar
  7. 7.
    Salvucci O, Tosato G (2012) Essential roles of EphB receptors and EphrinB ligands in endothelial cell function and angiogenesis. Adv Cancer Res 114:21–57. doi: 10.1016/B978-0-12-386503-8.00002-8 PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Pitulescu ME, Adams RH (2010) Eph/ephrin molecules–a hub for signaling and endocytosis. Genes Dev 24(22):2480–2492. doi: 10.1101/gad.1973910 PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Hirai H, Maru Y, Hagiwara K, Nishida J, Takaku F (1987) A novel putative tyrosine kinase receptor encoded by the eph gene. Science 238(4834):1717–1720PubMedCrossRefGoogle Scholar
  10. 10.
    Gerety SS, Anderson DJ (2002) Cardiovascular ephrinB2 function is essential for embryonic angiogenesis. Development 129(6):1397–1410PubMedGoogle Scholar
  11. 11.
    Gerety SS, Wang HU, Chen ZF, Anderson DJ (1999) Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol Cell 4(3):403–414PubMedCrossRefGoogle Scholar
  12. 12.
    Murai KK, Pasquale EB (2003) ‘Eph’ective signaling: forward, reverse and crosstalk. J Cell Sci 116(Pt 14):2823–2832. doi: 10.1242/jcs.00625 PubMedCrossRefGoogle Scholar
  13. 13.
    Daar IO (2012) Non-SH2/PDZ reverse signaling by ephrins. Semin Cell Dev Biol 23(1):65–74. doi: 10.1016/j.semcdb.2011.10.012 PubMedCrossRefGoogle Scholar
  14. 14.
    Pasquale EB (2008) Eph-ephrin bidirectional signaling in physiology and disease. Cell 133(1):38–52. doi: 10.1016/j.cell.2008.03.011 PubMedCrossRefGoogle Scholar
  15. 15.
    Himanen JP, Chumley MJ, Lackmann M, Li C, Barton WA, Jeffrey PD, Vearing C, Geleick D, Feldheim DA, Boyd AW, Henkemeyer M, Nikolov DB (2004) Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling. Nat Neurosci 7(5):501–509. doi: 10.1038/nn1237 PubMedCrossRefGoogle Scholar
  16. 16.
    Brambilla R, Bruckner K, Orioli D, Bergemann AD, Flanagan JG, Klein R (1996) Similarities and differences in the way transmembrane-type ligands interact with the Elk subclass of Eph receptors. Mol Cell Neurosci 8(2–3):199–209. doi: 10.1006/mcne.1996.0057 CrossRefGoogle Scholar
  17. 17.
    Lee HS, Mood K, Battu G, Ji YJ, Singh A, Daar IO (2009) Fibroblast growth factor receptor-induced phosphorylation of ephrinB1 modulates its interaction with Dishevelled. Mol Biol Cell 20(1):124–133. doi: 10.1091/mbc.E08-06-0662 PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Pasquale EB (2010) Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer 10(3):165–180. doi: 10.1038/nrc2806 PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Brantley-Sieders DM, Chen J (2004) Eph receptor tyrosine kinases in angiogenesis: from development to disease. Angiogenesis 7(1):17–28. doi: 10.1023/B:AGEN.0000037340.33788.87 PubMedCrossRefGoogle Scholar
  20. 20.
    Chrencik JE, Brooun A, Recht MI, Kraus ML, Koolpe M, Kolatkar AR, Bruce RH, Martiny-Baron G, Widmer H, Pasquale EB, Kuhn P (2006) Structure and thermodynamic characterization of the EphB4/Ephrin-B2 antagonist peptide complex reveals the determinants for receptor specificity. Structure 14(2):321–330. doi: 10.1016/j.str.2005.11.011 PubMedCrossRefGoogle Scholar
  21. 21.
    Kida Y, Ieronimakis N, Schrimpf C, Reyes M, Duffield JS (2013) EphrinB2 reverse signaling protects against capillary rarefaction and fibrosis after kidney injury. J Am Soc Nephrol (JASN) 24(4):559–572. doi: 10.1681/ASN.2012080871 CrossRefGoogle Scholar
  22. 22.
    Park I, Lee HS (2015) EphB/ephrinB signaling in cell adhesion and migration. Mol Cells 38(1):14–19. doi: 10.14348/molcells.2015.2116 PubMedCrossRefGoogle Scholar
  23. 23.
    Bikfalvi A (2006) Angiogenesis: health and disease. Ann Oncol 17(Suppl 10):x65–x70. doi: 10.1093/annonc/mdl239 PubMedCrossRefGoogle Scholar
  24. 24.
    Troidl K, Schaper W (2012) Arteriogenesis versus angiogenesis in peripheral artery disease. Diabetes/metabolism research and reviews 28(Suppl 1):27–29. doi: 10.1002/dmrr.2232 PubMedCrossRefGoogle Scholar
  25. 25.
    Cochain C, Channon KM, Silvestre JS (2013) Angiogenesis in the infarcted myocardium. Antioxid Redox Signal 18(9):1100–1113. doi: 10.1089/ars.2012.4849 PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Gale NW, Baluk P, Pan L, Kwan M, Holash J, DeChiara TM, McDonald DM, Yancopoulos GD (2001) Ephrin-B2 selectively marks arterial vessels and neovascularization sites in the adult, with expression in both endothelial and smooth-muscle cells. Dev Biol 230(2):151–160. doi: 10.1006/dbio.2000.0112 PubMedCrossRefGoogle Scholar
  27. 27.
    Bai J, Wang YJ, Liu L, Zhao YL (2014) Ephrin B2 and EphB4 selectively mark arterial and venous vessels in cerebral arteriovenous malformation. J Int Med Res 42(2):405–415. doi: 10.1177/0300060513478091 PubMedCrossRefGoogle Scholar
  28. 28.
    Kuijper S, Turner CJ, Adams RH (2007) Regulation of angiogenesis by Eph-ephrin interactions. Trends Cardiovasc Med 17(5):145–151. doi: 10.1016/j.tcm.2007.03.003 PubMedCrossRefGoogle Scholar
  29. 29.
    Abengozar MA, de Frutos S, Ferreiro S, Soriano J, Perez-Martinez M, Olmeda D, Marenchino M, Canamero M, Ortega S, Megias D, Rodriguez A, Martinez-Torrecuadrada JL (2012) Blocking ephrinB2 with highly specific antibodies inhibits angiogenesis, lymphangiogenesis, and tumor growth. Blood 119(19):4565–4576. doi: 10.1182/blood-2011-09-380006 PubMedCrossRefGoogle Scholar
  30. 30.
    Poliakov A, Cotrina M, Wilkinson DG (2004) Diverse roles of eph receptors and ephrins in the regulation of cell migration and tissue assembly. Dev Cell 7(4):465–480. doi: 10.1016/j.devcel.2004.09.006 PubMedCrossRefGoogle Scholar
  31. 31.
    Salvucci O, de la Luz Sierra M, Martina JA, McCormick PJ, Tosato G (2006) EphB2 and EphB4 receptors forward signaling promotes SDF-1-induced endothelial cell chemotaxis and branching remodeling. Blood 108(9):2914–2922. doi: 10.1182/blood-2006-05-023341 PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Yamanda S, Ebihara S, Asada M, Okazaki T, Niu K, Ebihara T, Koyanagi A, Yamaguchi N, Yagita H, Arai H (2009) Role of ephrinB2 in nonproductive angiogenesis induced by Delta-like 4 blockade. Blood 113(15):3631–3639. doi: 10.1182/blood-2008-07-170381 PubMedCrossRefGoogle Scholar
  33. 33.
    Palmer A, Zimmer M, Erdmann KS, Eulenburg V, Porthin A, Heumann R, Deutsch U, Klein R (2002) EphrinB phosphorylation and reverse signaling: regulation by Src kinases and PTP-BL phosphatase. Mol Cell 9(4):725–737PubMedCrossRefGoogle Scholar
  34. 34.
    Maekawa H, Oike Y, Kanda S, Ito Y, Yamada Y, Kurihara H, Nagai R, Suda T (2003) Ephrin-B2 induces migration of endothelial cells through the phosphatidylinositol-3 kinase pathway and promotes angiogenesis in adult vasculature. Arterioscler Thromb Vasc Biol 23(11):2008–2014. doi: 10.1161/01.ATV.0000096655.56262.56 PubMedCrossRefGoogle Scholar
  35. 35.
    Steinle JJ, Meininger CJ, Forough R, Wu G, Wu MH, Granger HJ (2002) Eph B4 receptor signaling mediates endothelial cell migration and proliferation via the phosphatidylinositol 3-kinase pathway. J Biol Chem 277(46):43830–43835. doi: 10.1074/jbc.M207221200 PubMedCrossRefGoogle Scholar
  36. 36.
    Adams RH, Wilkinson GA, Weiss C, Diella F, Gale NW, Deutsch U, Risau W, Klein R (1999) Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev 13(3):295–306PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Martiny-Baron G, Holzer P, Billy E, Schnell C, Brueggen J, Ferretti M, Schmiedeberg N, Wood JM, Furet P, Imbach P (2010) The small molecule specific EphB4 kinase inhibitor NVP-BHG712 inhibits VEGF driven angiogenesis. Angiogenesis 13(3):259–267. doi: 10.1007/s10456-010-9183-z PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Xue C, Chen Y, Huang Z, Ge Y, Wang H, Wang J (2014) EphB4 expression in pterygium is associated with microvessel density. Int J Clin Exp Med 7(11):4008–4015PubMedPubMedCentralGoogle Scholar
  39. 39.
    Huynh-Do U, Vindis C, Liu H, Cerretti DP, McGrew JT, Enriquez M, Chen J, Daniel TO (2002) Ephrin-B1 transduces signals to activate integrin-mediated migration, attachment and angiogenesis. J Cell Sci 115(Pt 15):3073–3081PubMedGoogle Scholar
  40. 40.
    Hamada K, Oike Y, Ito Y, Maekawa H, Miyata K, Shimomura T, Suda T (2003) Distinct roles of ephrin-B2 forward and EphB4 reverse signaling in endothelial cells. Arterioscler Thromb Vasc Biol 23(2):190–197PubMedCrossRefGoogle Scholar
  41. 41.
    Ruhrberg C, Gerhardt H, Golding M, Watson R, Ioannidou S, Fujisawa H, Betsholtz C, Shima DT (2002) Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev 16(20):2684–2698. doi: 10.1101/gad.242002 PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Sawamiphak S, Seidel S, Essmann CL, Wilkinson GA, Pitulescu ME, Acker T, Acker-Palmer A (2010) Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis. Nature 465(7297):487–491. doi: 10.1038/nature08995 PubMedCrossRefGoogle Scholar
  43. 43.
    Hainaud P, Contreres JO, Villemain A, Liu LX, Plouet J, Tobelem G, Dupuy E (2006) The role of the vascular endothelial growth factor-Delta-like 4 ligand/Notch4-ephrin B2 cascade in tumor vessel remodeling and endothelial cell functions. Cancer Res 66(17):8501–8510. doi: 10.1158/0008-5472.CAN-05-4226 PubMedCrossRefGoogle Scholar
  44. 44.
    Masumura T, Yamamoto K, Shimizu N, Obi S, Ando J (2009) Shear stress increases expression of the arterial endothelial marker ephrinB2 in murine ES cells via the VEGF-Notch signaling pathways. Arterioscler Thromb Vasc Biol 29(12):2125–2131. doi: 10.1161/ATVBAHA.109.193185 PubMedCrossRefGoogle Scholar
  45. 45.
    Sawamiphak S, Ritter M, Acker-Palmer A (2010) Preparation of retinal explant cultures to study ex vivo tip endothelial cell responses. Nat Protoc 5(10):1659–1665. doi: 10.1038/nprot.2010.130 PubMedCrossRefGoogle Scholar
  46. 46.
    Carter N, Nakamoto T, Hirai H, Hunter T (2002) EphrinA1-induced cytoskeletal re-organization requires FAK and p130(cas). Nat Cell Biol 4(8):565–573. doi: 10.1038/ncb823 PubMedGoogle Scholar
  47. 47.
    Zou JX, Wang B, Kalo MS, Zisch AH, Pasquale EB, Ruoslahti E (1999) An Eph receptor regulates integrin activity through R-Ras. Proc Natl Acad Sci USA 96(24):13813–13818PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Huynh-Do U, Stein E, Lane AA, Liu H, Cerretti DP, Daniel TO (1999) Surface densities of ephrin-B1 determine EphB1-coupled activation of cell attachment through alphavbeta3 and alpha5beta1 integrins. EMBO J 18(8):2165–2173. doi: 10.1093/emboj/18.8.2165 PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Kullander K, Klein R (2002) Mechanisms and functions of Eph and ephrin signalling. Nat Rev Mol Cell Biol 3(7):475–486. doi: 10.1038/nrm856 PubMedCrossRefGoogle Scholar
  50. 50.
    Hayashi S, Asahara T, Masuda H, Isner JM, Losordo DW (2005) Functional ephrin-B2 expression for promotive interaction between arterial and venous vessels in postnatal neovascularization. Circulation 111(17):2210–2218. doi: 10.1161/01.CIR.0000163566.07427.73 PubMedCrossRefGoogle Scholar
  51. 51.
    Erber R, Eichelsbacher U, Powajbo V, Korn T, Djonov V, Lin J, Hammes HP, Grobholz R, Ullrich A, Vajkoczy P (2006) EphB4 controls blood vascular morphogenesis during postnatal angiogenesis. EMBO J 25(3):628–641. doi: 10.1038/sj.emboj.7600949 PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Kim I, Ryu YS, Kwak HJ, Ahn SY, Oh JL, Yancopoulos GD, Gale NW, Koh GY (2002) EphB ligand, ephrinB2, suppresses the VEGF- and angiopoietin 1-induced Ras/mitogen-activated protein kinase pathway in venous endothelial cells. FASEB J 16(9):1126–1128. doi: 10.1096/fj.01-0805fje PubMedGoogle Scholar
  53. 53.
    Fuller T, Korff T, Kilian A, Dandekar G, Augustin HG (2003) Forward EphB4 signaling in endothelial cells controls cellular repulsion and segregation from ephrinB2 positive cells. J Cell Sci 116(Pt 12):2461–2470. doi: 10.1242/jcs.00426 PubMedCrossRefGoogle Scholar
  54. 54.
    Noren NK, Lu M, Freeman AL, Koolpe M, Pasquale EB (2004) Interplay between EphB4 on tumor cells and vascular ephrin-B2 regulates tumor growth. Proc Natl Acad Sci USA 101(15):5583–5588. doi: 10.1073/pnas.0401381101 PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Noren NK, Foos G, Hauser CA, Pasquale EB (2006) The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl-Crk pathway. Nat Cell Biol 8(8):815–825. doi: 10.1038/ncb1438 PubMedCrossRefGoogle Scholar
  56. 56.
    Othman-Hassan K, Patel K, Papoutsi M, Rodriguez-Niedenfuhr M, Christ B, Wilting J (2001) Arterial identity of endothelial cells is controlled by local cues. Dev Biol 237(2):398–409. doi: 10.1006/dbio.2001.0383 PubMedCrossRefGoogle Scholar
  57. 57.
    Obi S, Yamamoto K, Shimizu N, Kumagaya S, Masumura T, Sokabe T, Asahara T, Ando J (2009) Fluid shear stress induces arterial differentiation of endothelial progenitor cells. J Appl Physiol 106(1):203–211. doi: 10.1152/japplphysiol.00197.2008 PubMedCrossRefGoogle Scholar
  58. 58.
    Foo SS, Turner CJ, Adams S, Compagni A, Aubyn D, Kogata N, Lindblom P, Shani M, Zicha D, Adams RH (2006) Ephrin-B2 controls cell motility and adhesion during blood-vessel-wall assembly. Cell 124(1):161–173. doi: 10.1016/j.cell.2005.10.034 PubMedCrossRefGoogle Scholar
  59. 59.
    Korff T, Braun J, Pfaff D, Augustin HG, Hecker M (2008) Role of ephrinB2 expression in endothelial cells during arteriogenesis: impact on smooth muscle cell migration and monocyte recruitment. Blood 112(1):73–81. doi: 10.1182/blood-2007-12-128835 PubMedCrossRefGoogle Scholar
  60. 60.
    Makinen T, Adams RH, Bailey J, Lu Q, Ziemiecki A, Alitalo K, Klein R, Wilkinson GA (2005) PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev 19(3):397–410. doi: 10.1101/gad.330105 PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Wang Y, Nakayama M, Pitulescu ME, Schmidt TS, Bochenek ML, Sakakibara A, Adams S, Davy A, Deutsch U, Luthi U, Barberis A, Benjamin LE, Makinen T, Nobes CD, Adams RH (2010) Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature 465(7297):483–486. doi: 10.1038/nature09002 PubMedCrossRefGoogle Scholar
  62. 62.
    Ma X, Luo D, Li K, Liu R, Liu Y, Zhu T, Deng D, Zhou J, Meng L, Wang S, Ma D (2012) Suppression of EphB4 improves the inhibitory effect of mTOR shRNA on the biological behaviors of ovarian cancer cells by down-regulating Akt phosphorylation. J Huazhong Univ Sci Technol Med Sci = Hua zhong ke ji da xue xue bao Yi xue Ying De wen ban = Huazhong keji daxue xuebao Yixue Yingdewen ban 32(3):358–363. doi: 10.1007/s11596-012-0062-2 PubMedCrossRefGoogle Scholar
  63. 63.
    Steinle JJ, Meininger CJ, Chowdhury U, Wu G, Granger HJ (2003) Role of ephrin B2 in human retinal endothelial cell proliferation and migration. Cell Signal 15(11):1011–1017PubMedCrossRefGoogle Scholar
  64. 64.
    Hernandez-Resendiz S, Palma-Flores C, De Los Santos S, Roman-Anguiano NG, Flores M, de la Pena A, Flores PL, Fernandez GJ, Coral-Vazquez RM, Zazueta C (2015) Reduction of no-reflow and reperfusion injury with the synthetic 17beta-aminoestrogen compound Prolame is associated with PI3 K/Akt/eNOS signaling cascade. Basic Res Cardiol 110(2):464. doi: 10.1007/s00395-015-0464-y CrossRefGoogle Scholar
  65. 65.
    Zhang Y, Wang SJ, Han ZH, Li YQ, Xue JH, Gao DF, Wu XS, Wang CX (2014) PI3 K/AKT signaling pathway plays a role in enhancement of eNOS activity by recombinant human angiotensin converting enzyme 2 in human umbilical vein endothelial cells. Int J Clin Exp Pathol 7(11):8112–8117PubMedPubMedCentralGoogle Scholar
  66. 66.
    Hood J, Granger HJ (1998) Protein kinase G mediates vascular endothelial growth factor-induced Raf-1 activation and proliferation in human endothelial cells. J Biol Chem 273(36):23504–23508PubMedCrossRefGoogle Scholar
  67. 67.
    Kaur S, Kumar TR, Uruno A, Sugawara A, Jayakumar K, Kartha CC (2009) Genetic engineering with endothelial nitric oxide synthase improves functional properties of endothelial progenitor cells from patients with coronary artery disease: an in vitro study. Basic Res Cardiol 104(6):739–749. doi: 10.1007/s00395-009-0039-x PubMedCrossRefGoogle Scholar
  68. 68.
    Bir SC, Xiong Y, Kevil CG, Luo J (2012) Emerging role of PKA/eNOS pathway in therapeutic angiogenesis for ischaemic tissue diseases. Cardiovasc Res 95(1):7–18. doi: 10.1093/cvr/cvs143 PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Dimmeler S, Dernbach E, Zeiher AM (2000) Phosphorylation of the endothelial nitric oxide synthase at ser-1177 is required for VEGF-induced endothelial cell migration. FEBS Lett 477(3):258–262PubMedCrossRefGoogle Scholar
  70. 70.
    Goligorsky MS, Abedi H, Noiri E, Takhtajan A, Lense S, Romanov V, Zachary I (1999) Nitric oxide modulation of focal adhesions in endothelial cells. Am J Physiol 276(6 Pt 1):C1271–C1281PubMedGoogle Scholar
  71. 71.
    Aslam MI, Abraham J, Mansoor A, Druker BJ, Tyner JW, Keller C (2014) PDGFRbeta reverses EphB4 signaling in alveolar rhabdomyosarcoma. Proc Natl Acad Sci USA 111(17):6383–6388. doi: 10.1073/pnas.1403608111 PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Lee TH, Jung H, Park KH, Bang MH, Baek NI, Kim J (2014) Jaceosidin, a natural flavone, promotes angiogenesis via activation of VEGFR2/FAK/PI3K/AKT/NF-kappaB signaling pathways in endothelial cells. Exp Biol Med 239(10):1325–1334. doi: 10.1177/1535370214533883 CrossRefGoogle Scholar
  73. 73.
    Jouve N, Bachelier R, Despoix N, Blin MG, Matinzadeh MK, Poitevin S, Aurrand-Lions M, Fallague K, Bardin N, Blot-Chabaud M, Vely F, Dignat-George F, Leroyer AS (2014) CD146 mediates VEGF-induced melanoma cell extravasation through FAK activation. Int J Cancer. doi: 10.1002/ijc.29370 PubMedGoogle Scholar
  74. 74.
    Park BK, Zeng X, Glazer RI (2001) Akt1 induces extracellular matrix invasion and matrix metalloproteinase-2 activity in mouse mammary epithelial cells. Cancer Res 61(20):7647–7653PubMedGoogle Scholar
  75. 75.
    Kim D, Kim S, Koh H, Yoon SO, Chung AS, Cho KS, Chung J (2001) Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. FASEB J 15(11):1953–1962. doi: 10.1096/fj.01-0198com PubMedCrossRefGoogle Scholar
  76. 76.
    Xiao Z, Carrasco R, Kinneer K, Sabol D, Jallal B, Coats S, Tice DA (2012) EphB4 promotes or suppresses Ras/MEK/ERK pathway in a context-dependent manner: implications for EphB4 as a cancer target. Cancer Biol Ther 13(8):630–637. doi: 10.4161/cbt.20080 PubMedCrossRefGoogle Scholar
  77. 77.
    Haupaix N, Stolfi A, Sirour C, Picco V, Levine M, Christiaen L, Yasuo H (2013) p120RasGAP mediates ephrin/Eph-dependent attenuation of FGF/ERK signals during cell fate specification in ascidian embryos. Development 140(21):4347–4352. doi: 10.1242/dev.098756 PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Salvucci O, Maric D, Economopoulou M, Sakakibara S, Merlin S, Follenzi A, Tosato G (2009) EphrinB reverse signaling contributes to endothelial and mural cell assembly into vascular structures. Blood 114(8):1707–1716. doi: 10.1182/blood-2008-12-192294 PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Xu NJ, Henkemeyer M (2009) Ephrin-B3 reverse signaling through Grb4 and cytoskeletal regulators mediates axon pruning. Nat Neurosci 12(3):268–276. doi: 10.1038/nn.2254 PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Segura I, Essmann CL, Weinges S, Acker-Palmer A (2007) Grb4 and GIT1 transduce ephrinB reverse signals modulating spine morphogenesis and synapse formation. Nat Neurosci 10(3):301–310. doi: 10.1038/nn1858 PubMedCrossRefGoogle Scholar
  81. 81.
    Cowan CA, Henkemeyer M (2001) The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals. Nature 413(6852):174–179. doi: 10.1038/35093123 PubMedCrossRefGoogle Scholar
  82. 82.
    Bong YS, Lee HS, Carim-Todd L, Mood K, Nishanian TG, Tessarollo L, Daar IO (2007) ephrinB1 signals from the cell surface to the nucleus by recruitment of STAT3. Proc Natl Acad Sci USA 104(44):17305–17310. doi: 10.1073/pnas.0702337104 PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Lu Q, Sun EE, Klein RS, Flanagan JG (2001) Ephrin-B reverse signaling is mediated by a novel PDZ-RGS protein and selectively inhibits G protein-coupled chemoattraction. Cell 105(1):69–79PubMedCrossRefGoogle Scholar
  84. 84.
    Su Z, Xu P, Ni F (2004) Single phosphorylation of Tyr304 in the cytoplasmic tail of ephrin B2 confers high-affinity and bifunctional binding to both the SH2 domain of Grb4 and the PDZ domain of the PDZ-RGS3 protein. Eur J Biochem/FEBS 271(9):1725–1736. doi: 10.1111/j.1432-1033.2004.04078.x CrossRefGoogle Scholar
  85. 85.
    Lu Q, Sun EE, Flanagan JG (2004) Analysis of PDZ-RGS3 function in ephrin-B reverse signaling. Methods Enzymol 390:120–128. doi: 10.1016/S0076-6879(04)90008-0 PubMedCrossRefGoogle Scholar
  86. 86.
    Anger T, Klintworth N, Stumpf C, Daniel WG, Mende U, Garlichs CD (2007) RGS protein specificity towards Gq- and Gi/o-mediated ERK 1/2 and Akt activation, in vitro. J Biochem Mol Biol 40(6):899–910PubMedCrossRefGoogle Scholar
  87. 87.
    Bochenek ML, Dickinson S, Astin JW, Adams RH, Nobes CD (2010) Ephrin-B2 regulates endothelial cell morphology and motility independently of Eph-receptor binding. J Cell Sci 123(Pt 8):1235–1246. doi: 10.1242/jcs.061903 PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Chong LD, Park EK, Latimer E, Friesel R, Daar IO (2000) Fibroblast growth factor receptor-mediated rescue of x-ephrin B1-induced cell dissociation in Xenopus embryos. Mol Cell Biol 20(2):724–734PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Bruckner K, Pasquale EB, Klein R (1997) Tyrosine phosphorylation of transmembrane ligands for Eph receptors. Science 275(5306):1640–1643PubMedCrossRefGoogle Scholar
  90. 90.
    Thelemann A, Petti F, Griffin G, Iwata K, Hunt T, Settinari T, Fenyo D, Gibson N, Haley JD (2005) Phosphotyrosine signaling networks in epidermal growth factor receptor overexpressing squamous carcinoma cells. Mol Cell Proteomics 4(4):356–376. doi: 10.1074/mcp.M400118-MCP200 PubMedCrossRefGoogle Scholar
  91. 91.
    Morita S, Furube E, Mannari T, Okuda H, Tatsumi K, Wanaka A, Miyata S (2015) Vascular endothelial growth factor-dependent angiogenesis and dynamic vascular plasticity in the sensory circumventricular organs of adult mouse brain. Cell Tissue Res. doi: 10.1007/s00441-014-2080-9 Google Scholar
  92. 92.
    Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD, Wiegand SJ (2007) Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci USA 104(9):3219–3224. doi: 10.1073/pnas.0611206104 PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Liu ZJ, Shirakawa T, Li Y, Soma A, Oka M, Dotto GP, Fairman RM, Velazquez OC, Herlyn M (2003) Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol Cell Biol 23(1):14–25PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Watson O, Novodvorsky P, Gray C, Rothman AM, Lawrie A, Crossman DC, Haase A, McMahon K, Gering M, Van Eeden FJ, Chico TJ (2013) Blood flow suppresses vascular Notch signalling via dll4 and is required for angiogenesis in response to hypoxic signalling. Cardiovasc Res 100(2):252–261. doi: 10.1093/cvr/cvt170 PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Hayashi H, Kume T (2008) Foxc transcription factors directly regulate Dll4 and Hey2 expression by interacting with the VEGF-Notch signaling pathways in endothelial cells. PLoS ONE 3(6):e2401. doi: 10.1371/journal.pone.0002401 PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Grego-Bessa J, Luna-Zurita L, del Monte G, Bolos V, Melgar P, Arandilla A, Garratt AN, Zang H, Mukouyama YS, Chen H, Shou W, Ballestar E, Esteller M, Rojas A, Perez-Pomares JM, de la Pompa JL (2007) Notch signaling is essential for ventricular chamber development. Dev Cell 12(3):415–429. doi: 10.1016/j.devcel.2006.12.011 PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Scehnet JS, Jiang W, Kumar SR, Krasnoperov V, Trindade A, Benedito R, Djokovic D, Borges C, Ley EJ, Duarte A, Gill PS (2007) Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Blood 109(11):4753–4760. doi: 10.1182/blood-2006-12-063933 PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Sturz A, Bader B, Thierauch KH, Glienke J (2004) EphB4 signaling is capable of mediating ephrinB2-induced inhibition of cell migration. Biochem Biophys Res Commun 313(1):80–88PubMedCrossRefGoogle Scholar
  99. 99.
    Zamora DO, Davies MH, Planck SR, Rosenbaum JT, Powers MR (2005) Soluble forms of EphrinB2 and EphB4 reduce retinal neovascularization in a model of proliferative retinopathy. Invest Ophthalmol Vis Sci 46(6):2175–2182. doi: 10.1167/iovs.04-0983 PubMedCrossRefGoogle Scholar
  100. 100.
    Das A, Shergill U, Thakur L, Sinha S, Urrutia R, Mukhopadhyay D, Shah VH (2010) Ephrin B2/EphB4 pathway in hepatic stellate cells stimulates Erk-dependent VEGF production and sinusoidal endothelial cell recruitment. Am J Physiol Gastrointest Liver Physiol 298(6):G908–G915. doi: 10.1152/ajpgi.00510.2009 PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Blum S, Issbruker K, Willuweit A, Hehlgans S, Lucerna M, Mechtcheriakova D, Walsh K, von der Ahe D, Hofer E, Clauss M (2001) An inhibitory role of the phosphatidylinositol 3-kinase-signaling pathway in vascular endothelial growth factor-induced tissue factor expression. J Biol Chem 276(36):33428–33434. doi: 10.1074/jbc.M105474200 PubMedCrossRefGoogle Scholar
  102. 102.
    Hong CC, Kume T, Peterson RT (2008) Role of crosstalk between phosphatidylinositol 3-kinase and extracellular signal-regulated kinase/mitogen-activated protein kinase pathways in artery-vein specification. Circ Res 103(6):573–579. doi: 10.1161/CIRCRESAHA.108.180745 PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Iso T, Maeno T, Oike Y, Yamazaki M (2006) Doi H, Arai M, Kurabayashi M Dll4-selective Notch signaling induces ephrinB2 gene expression in endothelial cells. Biochem Biophys Res Commun 341(3):708–714. doi: 10.1016/j.bbrc.2006.01.020 PubMedCrossRefGoogle Scholar
  104. 104.
    Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW, Lin HC, Yancopoulos GD, Thurston G (2006) Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444(7122):1032–1037. doi: 10.1038/nature05355 PubMedCrossRefGoogle Scholar
  105. 105.
    Li JL, Harris AL (2009) Crosstalk of VEGF and Notch pathways in tumour angiogenesis: therapeutic implications. Front Biosci 14:3094–3110CrossRefGoogle Scholar
  106. 106.
    Gaengel K, Betsholtz C (2013) Endocytosis regulates VEGF signalling during angiogenesis. Nat Cell Biol 15(3):233–235. doi: 10.1038/ncb2705 PubMedCrossRefGoogle Scholar
  107. 107.
    Yang C, Guo Y, Jadlowiec CC, Li X, Lv W, Model LS, Collins MJ, Kondo Y, Muto A, Shu C, Dardik A (2013) Vascular endothelial growth factor-A inhibits EphB4 and stimulates delta-like ligand 4 expression in adult endothelial cells. J Surg Res 183(1):478–486. doi: 10.1016/j.jss.2013.01.009 PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Dimova I, Hlushchuk R, Makanya A, Styp-Rekowska B, Ceausu A, Flueckiger S, Lang S, Semela D, Le Noble F, Chatterjee S, Djonov V (2013) Inhibition of Notch signaling induces extensive intussusceptive neo-angiogenesis by recruitment of mononuclear cells. Angiogenesis 16(4):921–937. doi: 10.1007/s10456-013-9366-5 PubMedCrossRefGoogle Scholar
  109. 109.
    Katsuta H, Fukushima Y, Maruyama K, Hirashima M, Nishida K, Nishikawa S, Uemura A (2013) EphrinB2–EphB4 signals regulate formation and maintenance of funnel-shaped valves in corneal lymphatic capillaries. Invest Ophthalmol Vis Sci 54(6):4102–4108. doi: 10.1167/iovs.12-11436 PubMedCrossRefGoogle Scholar
  110. 110.
    Hanawa K, Ito K, Aizawa K, Shindo T, Nishimiya K, Hasebe Y, Tuburaya R, Hasegawa H, Yasuda S, Kanai H, Shimokawa H (2014) Low-intensity pulsed ultrasound induces angiogenesis and ameliorates left ventricular dysfunction in a porcine model of chronic myocardial ischemia. PLoS ONE 9(8):e104863. doi: 10.1371/journal.pone.0104863 PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Sergienko IV, Masenko VP, Semenova AE, Gabrusenko SA, Naumov VG, Belenkov IuN (2009) Effect of myocardial revascularization on dynamics of factors of angiogenesis in patients with ischemic heart disease. Kardiologiia 49(12):4–10Google Scholar
  112. 112.
    Mansson-Broberg A, Siddiqui AJ, Genander M, Grinnemo KH, Hao X, Andersson AB, Wardell E, Sylven C, Corbascio M (2008) Modulation of ephrinB2 leads to increased angiogenesis in ischemic myocardium and endothelial cell proliferation. Biochem Biophys Res Commun 373(3):355–359. doi: 10.1016/j.bbrc.2008.06.036 PubMedCrossRefGoogle Scholar
  113. 113.
    Zhu L, Qian L, Wang S, Wang T, Jiang L (2014) Expression of ephrinB2 and EphB4 in a neonatal rat model of periventricular white matter damage. J Perinat Med. doi: 10.1515/jpm-2014-0096 Google Scholar
  114. 114.
    Vihanto MM, Plock J, Erni D, Frey BM, Frey FJ, Huynh-Do U (2005) Hypoxia up-regulates expression of Eph receptors and ephrins in mouse skin. FASEB J 19(12):1689–1691. doi: 10.1096/fj.04-3647fje PubMedGoogle Scholar
  115. 115.
    Liu H, Devraj K, Moller K, Liebner S, Hecker M, Korff T (2014) EphrinB-mediated reverse signalling controls junctional integrity and pro-inflammatory differentiation of endothelial cells. Thromb Haemost 112(1):151–163. doi: 10.1160/TH13-12-1034 PubMedCrossRefGoogle Scholar
  116. 116.
    Schruefer R, Sulyok S, Schymeinsky J, Peters T, Scharffetter-Kochanek K, Walzog B (2006) The proangiogenic capacity of polymorphonuclear neutrophils delineated by microarray technique and by measurement of neovascularization in wounded skin of CD18-deficient mice. J Vasc Res 43(1):1–11. doi: 10.1159/000088975 PubMedCrossRefGoogle Scholar
  117. 117.
    Yuan K, Jin YT, Lin MT (2000) Expression of Tie-2, angiopoietin-1, angiopoietin-2, ephrinB2 and EphB4 in pyogenic granuloma of human gingiva implicates their roles in inflammatory angiogenesis. J Periodontal Res 35(3):165–171PubMedCrossRefGoogle Scholar
  118. 118.
    Yuan K, Hong TM, Chen JJ, Tsai WH, Lin MT (2004) Syndecan-1 up-regulated by ephrinB2/EphB4 plays dual roles in inflammatory angiogenesis. Blood 104(4):1025–1033. doi: 10.1182/blood-2003-09-3334 PubMedCrossRefGoogle Scholar
  119. 119.
    Yu G, Luo H, Wu Y, Wu J (2003) Ephrin B2 induces T cell costimulation. J Immunol 171(1):106–114PubMedCrossRefGoogle Scholar
  120. 120.
    Zamora DO, Babra B, Pan Y, Planck SR, Rosenbaum JT (2006) Human leukocytes express ephrinB2 which activates microvascular endothelial cells. Cell Immunol 242(2):99–109. doi: 10.1016/j.cellimm.2006.10.001 PubMedCrossRefGoogle Scholar
  121. 121.
    Sun QN, Wang YF, Guo ZK (2012) Reconstitution of myocardial lymphatic vessels after acute infarction of rat heart. Lymphology 45(2):80–86PubMedGoogle Scholar
  122. 122.
    Mahmoodzadeh S, Leber J, Zhang X, Jaisser F, Messaoudi S, Morano I, Furth PA, Dworatzek E, Regitz-Zagrosek V (2014) Cardiomyocyte-specific estrogen receptor alpha increases angiogenesis, lymphangiogenesis and reduces fibrosis in the female mouse heart post-myocardial infarction. J Cell Sci Ther 5(1):153. doi: 10.4172/2157-7013.1000153 PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Laine GA, Allen SJ (1991) Left ventricular myocardial edema. Lymph flow, interstitial fibrosis, and cardiac function. Circ Res 68(6):1713–1721. doi: 10.1161/01.RES.68.6.1713 PubMedCrossRefGoogle Scholar
  124. 124.
    Ishii M, Mueller I, Nakajima T, Pasquale EB, Ogawa K (2011) EphB signaling inhibits gap junctional intercellular communication and synchronized contraction in cultured cardiomyocytes. Basic Res Cardiol 106(6):1057–1068. doi: 10.1007/s00395-011-0219-3 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Du Yang
    • 1
  • Chunna Jin
    • 1
  • Hong Ma
    • 1
  • Mingyuan Huang
    • 1
  • Guo-Ping Shi
    • 2
  • Jianan Wang
    • 1
  • Meixiang Xiang
    • 1
  1. 1.Department of Cardiology, Cardiovascular Key Laboratory of Zhejiang Province, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
  2. 2.Department of Cardiovascular MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA

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