Skip to main content
SpringerLink
Log in

Pathogenic role and therapeutic potential of pleiotrophin in mouse models of ocular vascular disease

  • Original Paper
  • Published:
Angiogenesis Aims and scope Submit manuscript

Abstract

Angiogenic factors play an important role in the pathogenesis of diabetic retinopathy (DR), neovascular age-related macular degeneration (nAMD) and retinopathy of prematurity (ROP). Pleiotrophin, a well-known angiogenic factor, was recently reported to be upregulated in the vitreous fluid of patients with proliferative DR (PDR). However, its pathogenic role and therapeutic potential in ocular vascular diseases have not been defined in vivo. Here using corneal pocket assays, we demonstrated that pleiotrophin induced angiogenesis in vivo. To investigate the pathological role of pleiotrophin we used neutralizing antibody to block its function in multiple in vivo models of ocular vascular diseases. In a mouse model of DR, intravitreal injection of pleiotrophin-neutralizing antibody alleviated diabetic retinal vascular leakage. In a mouse model of oxygen-induced retinopathy (OIR), which is a surrogate model of ROP and PDR, we demonstrated that intravitreal injection of anti-pleiotrophin antibody prevented OIR-induced pathological retinal neovascularization and aberrant vessel tufts. Finally, pleiotrophin-neutralizing antibody ameliorated laser-induced choroidal neovascularization, a mouse model of nAMD, suggesting that pleiotrophin is involved in choroidal vascular disease. These findings suggest that pleiotrophin plays an important role in the pathogenesis of DR with retinal vascular leakage, ROP with retinal neovascularization and nAMD with choroidal neovascularization. The results also support pleiotrophin as a promising target for anti-angiogenic therapy.

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

Access this article

Log in via an institution

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
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T et al (2012) Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 35(3):556–564

    Article  PubMed  PubMed Central  Google Scholar 

  2. Beharry KD, Valencia GB, Lazzaro DR, Aranda JV (2016) Pharmacologic interventions for the prevention and treatment of retinopathy of prematurity. Semin Perinatol 40(3):189–202

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hellstrom A, Smith LE, Dammann O (2013) Retinopathy of prematurity. Lancet 382(9902):1445–1457

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wong WL, Su X, Li X, Cheung CM, Klein R, Cheng CY et al (2014) Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health 2(2):e106–e116

    Article  PubMed  Google Scholar 

  5. Votruba M, Gregor Z (2001) Neovascular age-related macular degeneration: present and future treatment options. Eye (Lond) 15(Pt 3):424–429

    Article  CAS  Google Scholar 

  6. Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP et al (2015) Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 372(13):1193–1203

    Article  Google Scholar 

  7. Kim LA, D’Amore PA (2012) A brief history of anti-VEGF for the treatment of ocular angiogenesis. Am J Pathol 181(2):376–379

    Article  PubMed  Google Scholar 

  8. Dedania VS, Bakri SJ (2015) Current perspectives on ranibizumab. Clin Ophthalmol 9:533–542

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Drolet DW, Green LS, Gold L, Janjic N (2016) Fit for the eye: aptamers in ocular disorders. Nucleic Acid Ther 26(3):127–146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mintz-Hittner HA, Kennedy KA, Chuang AZ, Group B-RC (2011) Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med 364(7):603–615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lepore D, Quinn GE, Molle F, Baldascino A, Orazi L, Sammartino M et al (2014) Intravitreal bevacizumab versus laser treatment in type 1 retinopathy of prematurity: report on fluorescein angiographic findings. Ophthalmology 121(11):2212–2219

    Article  PubMed  Google Scholar 

  12. Deuel TF, Zhang N, Yeh HJ, Silos-Santiago I, Wang ZY (2002) Pleiotrophin: a cytokine with diverse functions and a novel signaling pathway. Arch Biochem Biophys 397(2):162–171

    Article  CAS  PubMed  Google Scholar 

  13. Papadimitriou E, Mikelis C, Lampropoulou E, Koutsioumpa M, Theochari K, Tsirmoula S et al (2009) Roles of pleiotrophin in tumor growth and angiogenesis. Eur Cytokine Netw 20(4):180–190

    CAS  PubMed  Google Scholar 

  14. Raulo E, Chernousov MA, Carey DJ, Nolo R, Rauvala H (1994) Isolation of a neuronal cell surface receptor of heparin binding growth-associated molecule (HB-GAM). Identification as N-syndecan (syndecan-3). J Biol Chem 269(17):12999–13004

    CAS  PubMed  Google Scholar 

  15. Bernard-Pierrot I, Delbe J, Rouet V, Vigny M, Kerros ME, Caruelle D et al (2002) Dominant negative effectors of heparin affin regulatory peptide (HARP) angiogenic and transforming activities. J Biol Chem 277(35):32071–32077

    Article  CAS  PubMed  Google Scholar 

  16. Bermek O, Diamantopoulou Z, Polykratis A, Dos Santos C, Hamma-Kourbali Y, Burlina F et al (2007) A basic peptide derived from the HARP C-terminus inhibits anchorage-independent growth of DU145 prostate cancer cells. Exp Cell Res 313(19):4041–4050

    Article  CAS  PubMed  Google Scholar 

  17. Mikelis C, Sfaelou E, Koutsioumpa M, Kieffer N, Papadimitriou E (2009) Integrin alpha(v)beta(3) is a pleiotrophin receptor required for pleiotrophin-induced endothelial cell migration through receptor protein tyrosine phosphatase beta/zeta. FASEB J. 23(5):1459–1469

    Article  CAS  PubMed  Google Scholar 

  18. Kadomatsu K, Muramatsu T (2004) Midkine and pleiotrophin in neural development and cancer. Cancer Lett 204(2):127–143

    Article  CAS  PubMed  Google Scholar 

  19. Meng K, Rodriguez-Pena A, Dimitrov T, Chen W, Yamin M, Noda M et al (2000) Pleiotrophin signals increased tyrosine phosphorylation of beta beta-catenin through inactivation of the intrinsic catalytic activity of the receptor-type protein tyrosine phosphatase beta/zeta. Proc Natl Acad Sci USA 97(6):2603–2608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fang W, Hartmann N, Chow DT, Riegel AT, Wellstein A (1992) Pleiotrophin stimulates fibroblasts and endothelial and epithelial cells and is expressed in human cancer. J Biol Chem 267(36):25889–25897

    CAS  PubMed  Google Scholar 

  21. Zhu X, Bai Y, Yu W, Pan C, Jin E, Song D et al (2015) The effects of pleiotrophin in proliferative diabetic retinopathy. PLoS ONE 10(1):e0115523

    Article  PubMed  PubMed Central  Google Scholar 

  22. Rauvala H (1989) An 18-kd heparin-binding protein of developing brain that is distinct from fibroblast growth factors. EMBO J 8(10):2933–2941

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Perez-Pinera P, Berenson JR, Deuel TF (2008) Pleiotrophin, a multifunctional angiogenic factor: mechanisms and pathways in normal and pathological angiogenesis. Curr Opin Hematol 15(3):210–214

    Article  CAS  PubMed  Google Scholar 

  24. LeBlanc ME, Wang W, Chen X, Ji Y, Shakya A, Shen C et al (2016) The regulatory role of hepatoma-derived growth factor as an angiogenic factor in the eye. Mol Vis 22:374–386

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Liang CC, Park AY, Guan JL (2007) In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc 2(2):329–333

    Article  CAS  PubMed  Google Scholar 

  26. LeBlanc ME, Wang W, Caberoy NB, Chen X, Guo F, Alvarado G et al (2015) Hepatoma-derived growth factor-related protein-3 is a novel angiogenic factor. PLoS ONE 10(5):e0127904

    Article  PubMed  PubMed Central  Google Scholar 

  27. Heiss C, Wong ML, Block VI, Lao D, Real WM, Yeghiazarians Y et al (2008) Pleiotrophin induces nitric oxide dependent migration of endothelial progenitor cells. J Cell Physiol 215(2):366–373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Scheppke L, Aguilar E, Gariano RF, Jacobson R, Hood J, Doukas J et al (2008) Retinal vascular permeability suppression by topical application of a novel VEGFR2/Src kinase inhibitor in mice and rabbits. J Clin Invest 118(6):2337–2346

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Connor KM, Krah NM, Dennison RJ, Aderman CM, Chen J, Guerin KI et al (2009) Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis. Nat Protoc 4(11):1565–1573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Poor SH, Qiu Y, Fassbender ES, Shen S, Woolfenden A, Delpero A et al (2014) Reliability of the mouse model of choroidal neovascularization induced by laser photocoagulation. Invest Ophthalmol Vis Sci 55(10):6525–6534

    Article  CAS  PubMed  Google Scholar 

  31. Chan N, He S, Spee CK, Ishikawa K, Hinton DR (2015) Attenuation of choroidal neovascularization by histone deacetylase inhibitor. PLoS ONE 10(3):e0120587

    Article  PubMed  PubMed Central  Google Scholar 

  32. Fan JB, Liu W, Yuan K, Zhu XH, Xu DW, Chen JJ et al (2014) EGFR trans-activation mediates pleiotrophin-induced activation of Akt and Erk in cultured osteoblasts. Biochem Biophys Res Commun 447(3):425–430

    Article  CAS  PubMed  Google Scholar 

  33. Li J, Wei H, Chesley A, Moon C, Krawczyk M, Volkova M et al (2007) The pro-angiogenic cytokine pleiotrophin potentiates cardiomyocyte apoptosis through inhibition of endogenous AKT/PKB activity. J Biol Chem 282(48):34984–34993

    Article  CAS  PubMed  Google Scholar 

  34. Choudhuri R, Zhang HT, Donnini S, Ziche M, Bicknell R (1997) An angiogenic role for the neurokines midkine and pleiotrophin in tumorigenesis. Cancer Res 57(9):1814–1819

    CAS  PubMed  Google Scholar 

  35. Rask-Madsen C, King GL (2013) Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab 17(1):20–33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stahl A, Connor KM, Sapieha P, Chen J, Dennison RJ, Krah NM et al (2010) The mouse retina as an angiogenesis model. Invest Ophthalmol Vis Sci 51(6):2813–2826

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kim CB, D’Amore PA, Connor KM (2016) Revisiting the mouse model of oxygen-induced retinopathy. Eye Brain 8:67–79

    Article  PubMed  PubMed Central  Google Scholar 

  38. Raulo E, Julkunen I, Merenmies J, Pihlaskari R, Rauvala H (1992) Secretion and biological activities of heparin-binding growth-associated molecule. Neurite outgrowth-promoting and mitogenic actions of the recombinant and tissue-derived protein. J Biol Chem 267(16):11408–11416

    CAS  PubMed  Google Scholar 

  39. Delbe J, Vacherot F, Laaroubi K, Barritault D, Courty J (1995) Effect of heparin on bovine epithelial lens cell proliferation induced by heparin affin regulatory peptide. J Cell Physiol 164(1):47–54

    Article  CAS  PubMed  Google Scholar 

  40. Papadimitriou E, Heroult M, Courty J, Polykratis A, Stergiou C, Katsoris P (2000) Endothelial cell proliferation induced by HARP: implication of N or C terminal peptides. Biochem Biophys Res Commun 274(1):242–248

    Article  CAS  PubMed  Google Scholar 

  41. Mentlein R, Held-Feindt J (2002) Pleiotrophin, an angiogenic and mitogenic growth factor, is expressed in human gliomas. J Neurochem 83(4):747–753

    Article  CAS  PubMed  Google Scholar 

  42. Li YS, Milner PG, Chauhan AK, Watson MA, Hoffman RM, Kodner CM et al (1990) Cloning and expression of a developmentally regulated protein that induces mitogenic and neurite outgrowth activity. Science 250(4988):1690–1694

    Article  CAS  PubMed  Google Scholar 

  43. Tsutsui J, Uehara K, Kadomatsu K, Matsubara S, Muramatsu T (1991) A new family of heparin-binding factors: strong conservation of midkine (MK) sequences between the human and the mouse. Biochem Biophys Res Commun 176(2):792–797

    Article  CAS  PubMed  Google Scholar 

  44. Kuboyama K, Fujikawa A, Suzuki R, Noda M (2015) Inactivation of protein tyrosine phosphatase receptor type Z by pleiotrophin promotes remyelination through activation of differentiation of oligodendrocyte precursor cells. J Neurosci 35(35):12162–12171

    Article  CAS  PubMed  Google Scholar 

  45. Courty J, Dauchel MC, Caruelle D, Perderiset M, Barritault D (1991) Mitogenic properties of a new endothelial cell growth factor related to pleiotrophin. Biochem Biophys Res Commun 180(1):145–151

    Article  CAS  PubMed  Google Scholar 

  46. Kong Y, Bai PS, Nan KJ, Sun H, Chen NZ, Qi XG (2012) Pleiotrophin is a potential colorectal cancer prognostic factor that promotes VEGF expression and induces angiogenesis in colorectal cancer. Int J Colorectal Dis 27(3):287–298

    Article  PubMed  Google Scholar 

  47. Chauhan AK, Li YS, Deuel TF (1993) Pleiotrophin transforms NIH 3T3 cells and induces tumors in nude mice. Proc Natl Acad Sci USA 90(2):679–682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Besse S, Comte R, Frechault S, Courty J, de Joel L, Delbe J (2013) Pleiotrophin promotes capillary-like sprouting from senescent aortic rings. Cytokine 62(1):44–47

    Article  CAS  PubMed  Google Scholar 

  49. Zhang N, Zhong R, Perez-Pinera P, Herradon G, Ezquerra L, Wang ZY et al (2006) Identification of the angiogenesis signaling domain in pleiotrophin defines a mechanism of the angiogenic switch. Biochem Biophys Res Commun 343(2):653–658

    Article  CAS  PubMed  Google Scholar 

  50. Koch S, Tugues S, Li X, Gualandi L, Claesson-Welsh L (2011) Signal transduction by vascular endothelial growth factor receptors. Biochem J 437(2):169–183

    Article  CAS  PubMed  Google Scholar 

  51. Ramos JW (2008) The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells. Int J Biochem Cell Biol 40(12):2707–2719

    Article  CAS  PubMed  Google Scholar 

  52. Hu L, Wang J, Wang Y, Xu H (2016) An integrin alphavbeta3 antagonistic modified peptide inhibits tumor growth through inhibition of the ERK and AKT signaling pathways. Oncol Rep 36(4):1953–1962

    Article  CAS  PubMed  Google Scholar 

  53. Eishingdrelo H, Kongsamut S (2013) Minireview: targeting GPCR activated ERK pathways for drug discovery. Curr Chem Genom Transl Med 7:9–15

    Article  PubMed  PubMed Central  Google Scholar 

  54. Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J et al (1989) Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246(4935):1309–1312

    Article  CAS  PubMed  Google Scholar 

  55. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246(4935):1306–1309

    Article  CAS  PubMed  Google Scholar 

  56. Tokunaga CC, Mitton KP, Dailey W, Massoll C, Roumayah K, Guzman E et al (2014) Effects of anti-VEGF treatment on the recovery of the developing retina following oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 55(3):1884–1892

    Article  CAS  PubMed  Google Scholar 

  57. Zhang L, Kundu S, Feenstra T, Li X, Jin C, Laaniste L et al (2015) Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas. Sci Signal 8(406):ra125

    Article  PubMed  Google Scholar 

  58. Heroult M, Bernard-Pierrot I, Delbe J, Hamma-Kourbali Y, Katsoris P, Barritault D et al (2004) Heparin affin regulatory peptide binds to vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis. Oncogene 23(9):1745–1753

    Article  CAS  PubMed  Google Scholar 

  59. Koutsioumpa M, Poimenidi E, Pantazaka E, Theodoropoulou C, Skoura A, Megalooikonomou V et al (2015) Receptor protein tyrosine phosphatase beta/zeta is a functional binding partner for vascular endothelial growth factor. Mol Cancer 14:19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Papadimitriou E, Pantazaka E, Castana P, Tsalios T, Polyzos A, Beis D (2016) Pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta as regulators of angiogenesis and cancer. Biochim Biophys Acta 1866(2):252–265

    CAS  PubMed  Google Scholar 

  61. Kokolakis G, Mikelis C, Papadimitriou E, Courty J, Karetsou E, Katsoris P (2006) Effect of heparin affin regulatory peptide on the expression of vascular endothelial growth factor receptors in endothelial cells. Vivo. 20(5):629–635

    CAS  Google Scholar 

  62. Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V et al (1998) 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 273(46):30336–30343

    Article  CAS  PubMed  Google Scholar 

  63. Byeon SH, Lee SC, Choi SH, Lee HK, Lee JH, Chu YK et al (2010) Vascular endothelial growth factor as an autocrine survival factor for retinal pigment epithelial cells under oxidative stress via the VEGF-R2/PI3K/Akt. Invest Ophthalmol Vis Sci 51(2):1190–1197

    Article  PubMed  Google Scholar 

  64. Rosenstein JM, Mani N, Khaibullina A, Krum JM (2003) Neurotrophic effects of vascular endothelial growth factor on organotypic cortical explants and primary cortical neurons. J Neurosci 23(35):11036–11044

    CAS  PubMed  Google Scholar 

  65. LeBlanc ME, Wang W, Chen X, Caberoy NB, Guo F, Shen C et al (2017) Secretogranin III as a disease-associated ligand for antiangiogenic therapy of diabetic retinopathy. J Exp Med 214(4):1029–1047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Lynn KD, Roland CL, Brekken RA (2010) VEGF and pleiotrophin modulate the immune profile of breast cancer. Cancers (Basel) 2(2):970–988

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank F. Zhang and R. Wen for instrument support; G. Gaidosh for confocal service.

Funding

This work was supported by NIH R01GM094449 (W.L.), R21HD075372 (W.L.), R21EY027065 (W.L.), Special Scholar Award from Research to Prevent Blindness (RPB) (W.L.), American Heart Association Predoctoral Fellowship 14PRE18310014 (M.E.L) and 16PRE27250308 (M.E.L), NIH P30-EY014801 and an institutional grant from RPB.

Authors’ contribution

W.W., M.E.L., P.C., Y.L., M.B., H.T., S.R.S., performed most of the studies and analyzed data. X.P. carried out corneal pocket assay. M.B. H.T., S.R.S provide supportive experiments. W.L. designed experiments, analyzed data and wrote manuscript. K.W. provided reagents, advised on experimental design and revised manuscript.

Author information

Author notes

  1. Weiwen Wang and Michelle E. LeBlanc have contributed equally.

Authors and Affiliations

  1. Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL, USA

    Weiwen Wang, Michelle E. LeBlanc, Xiuping Chen, Ping Chen, Yanli Ji, Megan Brewer, Hong Tian, Samantha R. Spring & Wei Li

  2. Vascular Biology Institute, University of Miami School of Medicine, Miami, FL, USA

    Keith A. Webster & Wei Li

  3. Department of Ophthalmology, Zhongshan Hospital of Fudan University, Shanghai, China

    Xiuping Chen

  4. Department of Ophthalmology, Renji Hospital of Jiaotong University, Shanghai, China

    Ping Chen

  5. Department of Ophthalmology, Zhengzhou Eye Hospital, Zhengzhou, Henan, China

    Yanli Ji

  6. School of Public Health, Xinxiang Medical University, Xinxiang, Henan, China

    Hong Tian

Authors
  1. Weiwen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michelle E. LeBlanc
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiuping Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ping Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yanli Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Megan Brewer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hong Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Samantha R. Spring
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Keith A. Webster
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei Li.

Ethics declarations

Conflict of interest

The authors declare no competing or financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, W., LeBlanc, M.E., Chen, X. et al. Pathogenic role and therapeutic potential of pleiotrophin in mouse models of ocular vascular disease. Angiogenesis 20, 479–492 (2017). https://doi.org/10.1007/s10456-017-9557-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10456-017-9557-6

Keywords

Search

Navigation