Skip to main content
SpringerLink
Log in

VEGF neutralization can prevent and normalize arteriovenous malformations in an animal model for hereditary hemorrhagic telangiectasia 2

  • Brief Communication
  • Published:
Angiogenesis Aims and scope Submit manuscript

Abstract

Arteriovenous malformation (AVM) refers to a vascular anomaly where arteries and veins are directly connected through a complex, tangled web of abnormal AV fistulae without a normal capillary network. Hereditary hemorrhagic telangiectasia (HHT) types 1 and 2 arise from heterozygous mutations in endoglin (ENG) and activin receptor-like kinase 1 (ALK1), respectively. HHT patients possess AVMs in various organs, and telangiectases (small AVMs) along the mucocutaneous surface. Understanding why and how AVMs develop is crucial for developing therapies to inhibit the formation, growth, or maintenance of AVMs in HHT patients. Previously, we have shown that secondary factors such as wounding are required for Alk1-deficient vessels to develop skin AVMs. Here, we present evidences that AVMs establish from nascent arteries and veins rather than from remodeling of a preexistent capillary network in the wound-induced skin AVM model. We also show that VEGF can mimic the wound effect on skin AVM formation, and VEGF-neutralizing antibody can prevent skin AVM formation and ameliorate internal bleeding in Alk1-deficient adult mice. With topical applications at different stages of AVM development, we demonstrate that the VEGF blockade can prevent the formation of AVM and cease the progression of AVM development. Taken together, the presented experimental model is an invaluable system for precise molecular mechanism of action of VEGF blockades as well as for preclinical screening of drug candidates for epistaxis and gastrointestinal bleedings.

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.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Shovlin CL (2010) Hereditary haemorrhagic telangiectasia Pathophysiology, diagnosis and treatment. Blood Rev 24:203–219

    Article  PubMed  CAS  Google Scholar 

  2. Abdalla SA, Letarte M (2006) Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet 43:97–110

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. 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 (1996) Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 13:189–195

    Article  PubMed  CAS  Google Scholar 

  4. McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, Helmbold EA, Markel DS, McKinnon WC, Murrell J (1994) Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 8:345–351

    Article  PubMed  CAS  Google Scholar 

  5. Fleetwood IG, Steinberg GK (2002) Arteriovenous malformations. Lancet 359:863–873

    Article  PubMed  Google Scholar 

  6. Letteboer TG, Mager HJ, Snijder RJ, Lindhout D, Ploos van Amstel HK, Zanen P, Westermann KJ (2008) Genotype-phenotype relationship for localization and age distribution of telangiectases in hereditary hemorrhagic telangiectasia. Am J Med Genet A 146A:2733–2739

    Article  PubMed  Google Scholar 

  7. Karnezis TT, Davidson TM (2011) Efficacy of intranasal bevacizumab (Avastin) treatment in patients with hereditary hemorrhagic telangiectasia-associated epistaxis. Laryngoscope 121:636–638

    Article  PubMed  CAS  Google Scholar 

  8. Karnezis TT, Davidson TM (2012) Treatment of hereditary hemorrhagic telangiectasia with submucosal and topical bevacizumab therapy. Laryngoscope 122:495–497

    Article  PubMed  CAS  Google Scholar 

  9. Simonds J, Miller F, Mandel J, Davidson TM (2009) The effect of bevacizumab (Avastin) treatment on epistaxis in hereditary hemorrhagic telangiectasia. Laryngoscope 119:988–992

    Article  PubMed  CAS  Google Scholar 

  10. Dupuis-Girod S, Ginon I, Saurin JC, Marion D, Guillot E, Decullier E, Roux A, Carette MF, Gilbert-Dussardier B, Hatron PY, Lacombe P, Lorcerie B, Riviere S, Corre R, Giraud S, Bailly S, Paintaud G, Ternant D, Valette PJ, Plauchu H, Faure F (2012) Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output. JAMA 307:948–955

    Article  PubMed  CAS  Google Scholar 

  11. Hoag JB, Terry P, Mitchell S, Reh D, Merlo CA (2010) An epistaxis severity score for hereditary hemorrhagic telangiectasia. Laryngoscope 120:838–843

    Article  PubMed  Google Scholar 

  12. Park SO, Wankhede M, Lee YJ, Choi EJ, Fliess N, Choe SW, Oh SH, Walter G, Raizada MK, Sorg BS, Oh SP (2009) Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia. J Clin Invest 119:3487–3496

    PubMed  CAS  PubMed Central  Google Scholar 

  13. Walker EJ, Su H, Shen FX, Choi EJ, Oh SP, Chen G, Lawton MT, Kim H, Chen YM, Chen WQ, Young WL (2011) Arteriovenous malformation in the adult mouse brain resembling the human disease. Ann Neurol 69:954–962

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Lopez-Novoa JM, Bernabeu C (2010) The physiological role of endoglin in the cardiovascular system. Am J Physiol Heart Circ Physiol 299:H959–H974

    Article  PubMed  CAS  Google Scholar 

  15. Corti P, Young S, Chen CY, Patrick MJ, Rochon ER, Pekkan K, Roman BL (2011) Interaction between alk1 and blood flow in the development of arteriovenous malformations. Development 138:1573–1582

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Sorg BS, Moeller BJ, Donovan O, Cao Y, Dewhirst MW (2005) Hyperspectral imaging of hemoglobin saturation in tumor microvasculature and tumor hypoxia development. J Biomed Opt 10:44004

    Article  PubMed  Google Scholar 

  17. Sorg BS, Hardee ME, Agarwal N, Moeller BJ, Dewhirst MW (2008) Spectral imaging facilitates visualization and measurements of unstable and abnormal microvascular oxygen transport in tumors. J Biomed Opt 13:014026

    Article  PubMed  Google Scholar 

  18. Danhier F, Ansorena E, Silva JM, Coco R, Le Breton A, Preat V (2012) PLGA-based nanoparticles: An overview of biomedical applications. J Control Rel 161:505–522

    Article  CAS  Google Scholar 

  19. Acharya AP, Clare-Salzler MJ, Keselowsky BG (2009) A high-throughput microparticle microarray platform for dendritic cell-targeting vaccines. Biomaterials 30:4168–4177

    Article  PubMed  CAS  Google Scholar 

  20. Mattsbybaltzer I, Jakobsson A, Sorbo J, Norrby K (1994) Endotoxin Is Angiogenic. Int J Exp Pathol 75:191–196

    CAS  Google Scholar 

  21. Ramanathan M, Pinhal-Enfield G, Hao I, Leibovich SJ (2007) Synergistic up-regulation of vascular endothelial growth factor (VEGF) expression in macrophages by adenosine A(2A) receptor agonists and endotoxin involves transcriptional regulation via the hypoxia response element in the VEGF promoter. Mol Biol Cell 18:14–23

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Xiong M, Elson G, Legarda D, Leibovich SJ (1998) Production of vascular endothelial growth factor by murine macrophages: regulation by hypoxia, lactate, and the inducible nitric oxide synthase pathway. Am J Pathol 153:587–598

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Campa C, Kasman I, Ye W, Lee WP, Fuh G, Ferrara N (2008) Effects of an anti-VEGF-A monoclonal antibody on laser-induced choroidal neovascularization in mice: optimizing methods to quantify vascular changes. Invest Ophthalmol Vis Sci 49:1178–1183

    Article  PubMed  Google Scholar 

  24. Schonthaler HB, Huggenberger R, Wculek SK, Detmar M, Wagner EF (2009) Systemic anti-VEGF treatment strongly reduces skin inflammation in a mouse model of psoriasis. Proc Natl Acad Sci USA 106:21264–21269

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Walker EJ, Su H, Shen FX, Degos V, Jun K, Young WL (2012) Bevacizumab Attenuates VEGF-Induced Angiogenesis and Vascular Malformations in the Adult Mouse Brain. Stroke 43:1925–1930

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Choi EJ, Kim YH, Choe SW, Tak YG, Garrido-Martin EM, Chang M, Lee YJ, Oh SP (2013) Enhanced responses to angiogenic cues underlie the pathogenesis of hereditary hemorrhagic telangiectasia 2. Plos One 8

  27. Ricard N, Ciais D, Levet S, Subileau M, Mallet C, Zimmers TA, Lee SJ, Bidart M, Feige JJ, Bailly S (2012) BMP9 and BMP10 are critical for postnatal retinal vascular remodeling. Blood 119:6162–6171

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Larrivee B, Prahst C, Gordon E, del Toro R, Mathivet T, Duarte A, Simons M, Eichmann A (2012) ALK1 signaling inhibits angiogenesis by cooperating with the notch pathway. Dev Cell 22:489–500

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Kim JH, Peacock MR, George SC, Hughes CCW (2012) BMP9 induces EphrinB2 expression in endothelial cells through an Alk1-BMPRII/ActRII-ID1/ID3-dependent pathway: implications for hereditary hemorrhagic telangiectasia type II. Angiogenesis 15:497–509

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Davidson TM, Olitsky SE, Wei JL (2010) Hereditary hemorrhagic telangiectasia/avastin. Laryngoscope 120:432–435

    PubMed  Google Scholar 

  31. Ardelean DS, Jerkic M, Yin M, Peter M, Ngan B, Kerbel RS, Foster FS, Letarte M (2014) Endoglin and activin receptor-like kinase 1 heterozygous mice have a distinct pulmonary and hepatic angiogenic profile and response to anti-VEGF treatment. Angiogenesis 17:129–146

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Genentech (Roche) for providing G6.31 antibodies. This work is supported by NIH Grant HL64024 (S.P.O), HHT Foundation International Inc (S.P.O), and AHA predoctoral fellowship (Y.H.K.).

Conflict of interest

The authors have declared that no conflict of interest exists.

Author information

Authors and Affiliations

  1. Department of Physiology and Functional Genomics, University of Florida College of Medicine, P.O. Box 100274, Gainesville, FL, 32610, USA

    Chul Han, Se-woon Choe, Yong Hwan Kim & S. Paul Oh

  2. Department of Biomedical Engineering, Tongmyong University, Busan, Republic of Korea

    Se-woon Choe

  3. J. Crayton Pruitt Family Department of Biomedical Engineering, College of Engineering, University of Florida, Gainesville, FL, 32611, USA

    Abhinav P. Acharya, Benjamin G. Keselowsky & Brian S. Sorg

  4. World Class University program, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea

    Young-Jae Lee & S. Paul Oh

Authors
  1. Chul Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Se-woon Choe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yong Hwan Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Abhinav P. Acharya
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Benjamin G. Keselowsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Brian S. Sorg
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Young-Jae Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S. Paul Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. Paul Oh.

Additional information

Chul Han and Se-woon Choe have contributed equally to this works.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 4354 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Han, C., Choe, Sw., Kim, Y.H. et al. VEGF neutralization can prevent and normalize arteriovenous malformations in an animal model for hereditary hemorrhagic telangiectasia 2. Angiogenesis 17, 823–830 (2014). https://doi.org/10.1007/s10456-014-9436-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10456-014-9436-3

Keywords

Search

Navigation