Skip to main content

Advertisement

SpringerLink
Log in

Increase of circulating endothelial cells in patients with Hereditary Hemorrhagic Telangiectasia

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by vascular malformations. The genes known to be associated with HHT include ENG (HHT1), ACVRL1 (HHT2) and SMAD4 (JPHT). It has been reported that circulating CD34+ cell subsets repair damaged vessels. To investigate whether mobilization of these cells is present in the peripheral blood (PB) of HTT patients, we analyzed CD34+ cells, CD34+VEGFR-2+ progenitor or mature endothelial cells, and CD34+CD133+VEGFR-2− hematopoietic progenitor cells (HPCs). Cytofluorimetric analysis was performed in 150 HTT patients and 43 healthy subjects (CTRLs). In HTT patients, PB CD34+ cells were significantly increased; the frequency of endothelial cells was higher (P = 0.002), while the frequency of CD34+CD133+VEGFR-2− HPCs was lower (P = 0.00007) than in CTRLs. Results were comparable in patients with ENG or ACVRL1 gene mutation; in patients with ENG mutation, the frequency of the cell subsets inversely correlated with the age of the patients at time of sampling (CD34+), disease duration (CD34+VEGFR-2+), and age at disease onset (CD34+CD133+ VEGFR-2−). In conclusion, HHT patients show an increase of circulating endothelial cells and a decrease of HPCs. In patients with ENG mutation, the frequency of CD34+ endothelial cells correlates with specific clinical characteristics suggesting that their active turnover characterizes the initial phase of the disease.

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

Similar content being viewed by others

Abbreviations

HHT:

Hereditary Hemorrhagic Telangiectasia

AVMs:

Arteriovenous malformations

TGFβ:

Transforming growth factor β

BMPs:

Bone morphogenetic proteins

ECs:

Endothelial cells

HPCs:

Hematopoietic progenitor cells

EPCs:

Endothelial progenitor cells

PB:

Peripheral blood

CTRLs:

Healthy subjects

References

  1. Faughnan M, Palda V, Garcia-Tsao G, Geisthoff U, McDonald J, Proctor D, Spears J, Brown D, Buscarini E, Chesnutt M, Cottin V, Ganguly A, Gossage J, Guttmacher A, Hyland R, Kennedy S, Korzenik J, Mager J, Ozanne A, Piccirillo J, Picus D, Plauchu H, Porteous M, Pyeritz R, Ross D, Sabba C, Swanson K, Terry P, Wallace M, Westermann C, White R, Young L, Zarrabeitia R. International guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia. J Med Genet. 2011;48:73–87.

  2. Shovlin CL. Hereditary haemorrhagic telangiectasia: pathophysiology, diagnosis and treatment. Blood Rev. 2010;24:203–19.

    Article  CAS  PubMed  Google Scholar 

  3. Govani FS, Shovlin CL. Hereditary haemorrhagic telangiectasia: a clinical and scientific review. Eur J Hum Genet. 2009;17:860–71.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Lesca G, Genin E, Blachier C, Olivieri C, Coulet F, Brunet G, Dupuis-Girod S, Buscarini E, Soubrier F, Calender A, Danesino C, Giraud S, Plauchu H, Network F-IH. Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients. Eur J Hum Genet. 2008;16:742–9.

    Article  CAS  PubMed  Google Scholar 

  5. Lesca G, Olivieri C, Burnichon N, Pagella F, Carette MF, Gilbert-Dussardier B, Goizet C, Roume J, Rabilloud M, Saurin JC, Cottin V, Honnorat J, Coulet F, Giraud S, Calender A, Danesino C, Buscarini E, Plauchu H, Network F–I–R–O. Genotype–phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French–Italian HHT network. Genet Med. 2007;9:14–22.

    Article  PubMed  Google Scholar 

  6. Gallione C, Scheessele E, Reinhardt D, Duits A, Berg J, Westermann C, Marchuk D. Two common endoglin mutations in families with hereditary hemorrhagic telangiectasia in The Netherlands antilles: evidence for a founder effect. Hum Genet. 2000;107:40–4.

    Article  CAS  PubMed  Google Scholar 

  7. Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJ, Kjeldsen AD, Plauchu H. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu–Osler–Weber syndrome). Am J Med Genet. 2000;91:66–7.

    Article  CAS  PubMed  Google Scholar 

  8. McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, Helmbold EA, Markel DS, McKinnon WC, Murrell J, et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet. 1994;8:345–51.

    Article  CAS  PubMed  Google Scholar 

  9. Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I, Yoon SJ, Stenzel TT, Speer M, Pericak-Vance MA, Diamond A, Guttmacher AE, Jackson CE, Attisano L, Kucherlapati R, Porteous ME, Marchuk DA. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet. 1996;13:189–95.

    Article  CAS  PubMed  Google Scholar 

  10. Trembath R, Thomson J, Machado R, Morgan N, Atkinson C, Winship I, Simonneau G, Galie N, Loyd J, Humbert M, Nichols W, Morrell N, Berg J, Manes A, McGaughran J, Pauciulo M, Wheeler L. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med. 2001;345:325–34.

    Article  CAS  PubMed  Google Scholar 

  11. Olivieri C, Lanzarini L, Pagella F, Semino L, Corno S, Valacca C, Plauchu H, Lesca G, Barthelet M, Buscarini E, Danesino C. Echocardiographic screening discloses increased values of pulmonary artery systolic pressure in 9 of 68 unselected patients affected with hereditary hemorrhagic telangiectasia. Genet Med. 2006;8:183–90.

    Article  PubMed  Google Scholar 

  12. Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, Mitchell G, Drouin E, Westermann CJ, Marchuk DA. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004;363:852–9.

    Article  CAS  PubMed  Google Scholar 

  13. Cole SG, Begbie ME, Wallace GM, Shovlin CL. A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5. J Med Genet. 2005;42:577–82.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Bayrak-Toydemir P, McDonald J, Akarsu N, Toydemir RM, Calderon F, Tuncali T, Tang W, Miller F, Mao R. A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7. Am J Med Genet A. 2006;140:2155–62.

    Article  PubMed  Google Scholar 

  15. David L, Mallet C, Mazerbourg S, Feige JJ, Bailly S. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood. 2007;109:1953–61.

    Article  CAS  PubMed  Google Scholar 

  16. Fu Y, Chang A, Chang L, Niessen K, Eapen S, Setiadi A, Karsan A. Differential regulation of transforming growth factor beta signaling pathways by notch in human endothelial cells. J Biol Chem. 2009;284:19452–62.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Lebrin F, Srun S, Raymond K, Martin S, van den Brink S, Freitas C, Bréant C, Mathivet T, Larrivée B, Thomas JL, Arthur HM, Westermann CJ, Disch F, Mager JJ, Snijder RJ, Eichmann A, Mummery CL. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med. 2010;16:420–8.

    Article  CAS  PubMed  Google Scholar 

  18. Fernandez-L A, Sanz-Rodriguez F, Zarrabeitia R, Pérez-Molino A, Hebbel R, Nguyen J, Bernabéu C, Botella L. Blood outgrowth endothelial cells from hereditary haemorrhagic telangiectasia patients reveal abnormalities compatible with vascular lesions. Cardiovasc Res. 2005;68:235–48.

    Article  CAS  PubMed  Google Scholar 

  19. Zucco L, Zhang Q, Kuliszewski MA, Kandic I, Faughnan ME, Stewart DJ, Kutryk MJ. Circulating angiogenic cell dysfunction in patients with hereditary hemorrhagic telangiectasia. PLoS One. 2014;9:e89927.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Yoder MC, Mead LE, Prater D, Krier TR, Mroueh KN, Li F, Krasich R, Temm CJ, Prchal JT, Ingram DA. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood. 2007;109:1801–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Yoder MC. Human endothelial progenitor cells. Cold Spring Harb Perspect Med. 2012;2:a006692.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Case J, Mead LE, Bessler WK, Prater D, White HA, Saadatzadeh MR, Bhavsar JR, Yoder MC, Haneline LS, Ingram DA. Human CD34+AC133+VEGFR-2+ cells are not endothelial progenitor cells but distinct, primitive hematopoietic progenitors. Exp Hematol. 2007;35:1109–18.

    Article  CAS  PubMed  Google Scholar 

  23. Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, Böhm M, Nickenig G. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med. 2005;353:999–1007.

    Article  CAS  PubMed  Google Scholar 

  24. Peichev M, Naiyer AJ, Pereira D, Zhu Z, Lane WJ, Williams M, Oz MC, Hicklin DJ, Witte L, Moore MA, Rafii S. Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood. 2000;95:952–8.

    CAS  PubMed  Google Scholar 

  25. Faughnan ME, Palda VA, Garcia-Tsao G, Geisthoff UW, McDonald J, Proctor DD, Spears J, Brown DH, Buscarini E, Chesnutt MS, Cottin V, Ganguly A, Gossage JR, Guttmacher AE, Hyland RH, Kennedy SJ, Korzenik J, Mager JJ, Ozanne AP, Piccirillo JF, Picus D, Plauchu H, Porteous ME, Pyeritz RE, Ross DA, Sabba C, Swanson K, Terry P, Wallace MC, Westermann CJ, White RI, Young LH, Zarrabeitia R, Group HHTFI-GW. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet. 2011;48:73–87.

    Article  CAS  PubMed  Google Scholar 

  26. Olivieri C, Pagella F, Semino L, Lanzarini L, Valacca C, Pilotto A, Corno S, Scappaticci S, Manfredi G, Buscarini E, Danesino C. Analysis of eng and ACVRL1 genes in 137 HHT italian families identifies 76 different mutations (24 novel). Comparison with other European studies. J Hum Genet. 2007;52:820–9.

    Article  CAS  PubMed  Google Scholar 

  27. Prater DN, Case J, Ingram DA, Yoder MC. Working hypothesis to redefine endothelial progenitor cells. Leukemia. 2007;21:1141–9.

    Article  CAS  PubMed  Google Scholar 

  28. Borges L, Iacovino M, Mayerhofer T, Koyano-Nakagawa N, Baik J, Garry DJ, Kyba M, Letarte M, Perlingeiro RC. A critical role for endoglin in the emergence of blood during embryonic development. Blood. 2012;119:5417–28.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Chen CZ, Li M, de Graaf D, Monti S, Göttgens B, Sanchez MJ, Lander ES, Golub TR, Green AR, Lodish HF. Identification of endoglin as a functional marker that defines long-term repopulating hematopoietic stem cells. Proc Natl Acad Sci USA. 2002;99:15468–73.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Buckley CD, Amft N, Bradfield PF, Pilling D, Ross E, Arenzana-Seisdedos F, Amara A, Curnow SJ, Lord JM, Scheel-Toellner D, Salmon M. Persistent induction of the chemokine receptor CXCR4 by TGF-beta 1 on synovial t cells contributes to their accumulation within the rheumatoid synovium. J Immunol. 2000;165:3423–9.

    Article  CAS  PubMed  Google Scholar 

  31. Scheubel RJ, Zorn H, Silber RE, Kuss O, Morawietz H, Holtz J, Simm A. Age-dependent depression in circulating endothelial progenitor cells in patients undergoing coronary artery bypass grafting. J Am Coll Cardiol. 2003;42:2073–80.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We wish to thank the Patients who collaborate to this research.

Conflict of interest

The authors declare not to have any conflict of interest.

Financial support

CC CD and CO are funded by the charity Italian HHT Patients’. Foundation: Associazione FONDAZIONE ITALIANA HHT “Onilde Carini”.

Author information

Authors and Affiliations

  1. Laboratori Sperimentali di Ricerca Area Biotecnologie, IRCCS Fondazione “Policlinico S. Matteo”, Viale Golgi 19, 27100, Pavia, Italy

    Margherita Massa

  2. Unità di Biologia Generale e Genetica Medica, Dipartimento di Medicina Molecolare, Università di Pavia, Via Forlanini 14, 27100, Pavia, Italy

    Cecilia Canzonieri, Cesare Danesino & Carla Olivieri

  3. Laboratori Sperimentali di Ricerca Area Biotecnologie, Centro per lo Studio e la Cura della Mielofibrosi, IRCCS Fondazione “Policlinico S. Matteo”, Viale Golgi 19, 27100, Pavia, Italy

    Rita Campanelli, Gabriela Fois & Vittorio Rosti

  4. Dipartimento di Cardiologia, IRCCS Fondazione “Policlinico S. Matteo”, Viale Golgi 19, 27100, Pavia, Italy

    Federica Ornati

  5. Unità di Otorinolaringoiatria, Dipartimento di Area Chirurgico-Specialistica, IRCCS Fondazione “Policlinico S. Matteo”and University of Pavia, Viale Golgi 19, 27100, Pavia, Italy

    Fabio Pagella & Elina Matti

  6. Dipartimento di Gastroenterologia, Ospedale Maggiore di Crema, Largo Ugo Dossena 2, 26013, Crema (CR), Italy

    Elisabetta Buscarini

Authors
  1. Margherita Massa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cecilia Canzonieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rita Campanelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Federica Ornati
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gabriela Fois
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fabio Pagella
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elina Matti
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Elisabetta Buscarini
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Cesare Danesino
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Vittorio Rosti
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Carla Olivieri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carla Olivieri.

Additional information

C. Canzonieri and R. Campanelli equally contributed to experimental work.

V. Rosti and C. Olivieri equally contributed to writing the paper.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Massa, M., Canzonieri, C., Campanelli, R. et al. Increase of circulating endothelial cells in patients with Hereditary Hemorrhagic Telangiectasia. Int J Hematol 101, 23–31 (2015). https://doi.org/10.1007/s12185-014-1698-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-014-1698-4

Keywords

Search

Navigation