Skip to main content
SpringerLink
Log in

TGF-β in Vascular Pathobiology

  • Chapter
  • First Online:
Textbook of Vascular Medicine

  • 1716 Accesses

Abstract

The transforming growth factor (TGF)-β superfamily includes 32 cytokines that tightly regulate vascular cell behaviour such as proliferation, migration, apoptosis, differentiation and extracellular matrix (ECM) maintenance, production and remodelling. Superfamily ligands signal via distinct type I and type II transmembrane serine/threonine kinase receptors activating canonical receptor-regulated (R)-s-mothers against decapentaplegic (SMAD) signalling and non-canonical signalling pathways. Normal vascular morphogenesis and homeostasis depend on intact TGF-β superfamily signalling. Genetic studies have demonstrated that defects in genes encoding TGF-β superfamily members predispose or are causally linked to certain hereditary vascular disorders (HVDs) such as hereditary haemorrhagic telangiectasia (HHT), hereditary pulmonary arterial hypertension (HPAH) and Loeys-Dietz syndrome (LDS). These discoveries have led to a better understanding of HVD pathogenesis giving rise to novel drug treatment strategies continuously improving life expectancy and the quality of life of affected patients. In addition, recent studies have discovered that the type I receptor activin-like kinase (ALK)1 and the type III co-receptor endoglin (ENG) promote tumour angiogenesis prompting the development of the ALK1 ligand trap dalantercept, the neutralising ALK1 antibody PF-03446962 and the monoclonal ENG antibody carotuximab. These novel anti-angiogenic cancer drugs have been or are currently being tested in phase I, II and III clinical trials for patients with advanced solid tumours.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. David CJ, Massagué J. Contextual determinants of TGFβ action in development, immunity and cancer. Nat Rev Mol Cell Biol. 2018;19(7):419–35.

    Article  CAS  Google Scholar 

  2. Martelossi Cebinelli GC, Paiva Trugilo K, Badaró Garcia S, Brajão de Oliveira K. TGF-β1 functional polymorphisms: a review. Eur Cytokine Netw. 2016;27(4):81–9.

    PubMed  Google Scholar 

  3. Bobik A. Transforming growth factor-betas and vascular disorders. Arterioscler Thromb Vasc Biol. 2006;26(8):1712–20.

    Article  CAS  Google Scholar 

  4. ten Dijke P, Arthur HM. Extracellular control of TGFbeta signalling in vascular development and disease. Nat Rev Mol Cell Biol. 2007;8(11):857–69.

    Article  Google Scholar 

  5. Roman BL, Hinck AP. ALK1 signaling in development and disease: new paradigms. Cell Mol Life Sci. 2017;74(24):4539–45.

    Article  CAS  Google Scholar 

  6. Pardali E, Goumans MJ, ten Dijke P. Signaling by members of the TGF-beta family in vascular morphogenesis and disease. Trends Cell Biol. 2010;20(9):556–67.

    Article  CAS  Google Scholar 

  7. Zuazo-Gaztelu I, Casanovas O. Unraveling the role of angiogenesis in cancer ecosystems. Front Oncol. 2018;8:1–13.

    Article  Google Scholar 

  8. Dickson MC, Martin JS, Cousins FM, Kulkarni AB, Karlsson S, Akhurst RJ. Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development. 1995;121(6):1845–54.

    CAS  PubMed  Google Scholar 

  9. Adams RH, Alitalo K. Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol. 2007;8(6):464–78.

    Article  CAS  Google Scholar 

  10. Krock BL, Skuli N, Simon MC. Hypoxia-induced angiogenesis: good and evil. Genes Cancer. 2011;2(12):1117–33.

    Article  Google Scholar 

  11. Pardali E, ten Dijke P. TGFβ signaling and cardiovascular diseases. Int J Biol Sci. 2012;8(2):195–213.

    Article  CAS  Google Scholar 

  12. Levet S, Ouarné M, Ciais D, Coutton C, Subileau M, Mallet C, et al. BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus. Proc Natl Acad Sci U S A. 2015;112(25):E3207–15.

    Article  CAS  Google Scholar 

  13. Chen H, Shi S, Acosta L, Li W, Lu J, Bao S, Chen Z, et al. BMP10 is essential for maintaining cardiac growth during murine cardiogenesis. Development. 2004;131(9):2219–31.

    Article  CAS  Google Scholar 

  14. Kritharis A, Al-Samkari H, Kuter DJ. Hereditary hemorrhagic telangiectasia: diagnosis and management from the hematologist’s perspective. Haematologica. 2018;103(9):1433–43.

    Article  CAS  Google Scholar 

  15. Ruiz-Llorente L, Gallardo-Vara E, Rossi E, Smadja DM, Botella LM, Bernabeu C. Endoglin and alk1 as therapeutic targets for hereditary hemorrhagic telangiectasia. Expert Opin Ther Targets. 2017;21(10):933–47.

    Article  CAS  Google Scholar 

  16. Mahmoud M, Allinson KR, Zhai Z, Oakenfull R, Ghandi P, Adams RH, et al. Pathogenesis of arteriovenous malformations in the absence of endoglin. Circ Res. 2010;106(8):1425–33.

    Article  CAS  Google Scholar 

  17. Park SO, Wankhede M, Lee YJ, Choi EJ, Fliess N, Choe SW, et al. Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia. J Clin Invest. 2009;119(11):3487–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Dupuis-Girod S, Ginon I, Saurin JC, Marion D, Guillot E, Decullier E, et al. Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output. JAMA. 2012;307(9):948–55.

    Article  CAS  Google Scholar 

  19. Iyer VN, Apala DR, Pannu BS, Kotecha A, Brinjikji W, Leise MD, et al. Intravenous bevacizumab for refractory hereditary hemorrhagic telangiectasia-related epistaxis and gastrointestinal bleeding. Mayo Clin Proc. 2018;93(2):155–66.

    Article  CAS  Google Scholar 

  20. Lebrin F, Srun S, Raymond K, Martin S, Van Den Brink S, Freitas C, et al. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med. 2010;16(4):420–8.

    Article  CAS  Google Scholar 

  21. Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2015;46(6):903–75.

    Article  Google Scholar 

  22. Frump A, Prewitt A, de Caestecker M. BMPR2 mutations and endothelial dysfunction in pulmonary arterial hypertension. Pulm Circ. 2018;8(2):204589401876584.

    Article  Google Scholar 

  23. Girerd B, Weatherald J, Montani D, Humbert M. Heritable pulmonary hypertension: from bench to bedside. Eur Respir Rev. 2017;26(145):1–9.

    Article  Google Scholar 

  24. Soubrier F, Chung WK, Machado R, Grünig E, Aldred M, Geraci M, et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62(25):D13–21.

    Article  CAS  Google Scholar 

  25. Thomas M, Docx C, Holmes AM, Beach S, Duggan N, England K, et al. Activin-like kinase 5 (ALK5) mediates abnormal proliferation of vascular smooth muscle cells from patients with familial pulmonary arterial hypertension and is involved in the progression of experimental pulmonary arterial hypertension induced by monocrotaline. Am J Pathol. 2009;174(2):380–9.

    Article  CAS  Google Scholar 

  26. Yeager ME, Halley GR, Golpon HA, Voelkel NF, Tuder RM. Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension. Circ Res. 2001;88(1):E2–E11.

    Article  CAS  Google Scholar 

  27. Cannaerts E, van de Beek G, Verstraeten A, Van Laer L, Loeys B. TGF-β signalopathies as a paradigm for translational medicine. Eur J Med Genet. 2015;58(12):695–703.

    Article  Google Scholar 

  28. MacCarrick G, Black JH, Bowdin S, El-Hamamsy I, Frischmeyer-Guerrerio PA, Guerrerio AL, et al. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med. 2014;16(8):576–87.

    Article  Google Scholar 

  29. Takeda N, Yagi H, Hara H, Fujiwara T, Fujita D, Nawata K, et al. Pathophysiology and Management of Cardiovascular Manifestations in Marfan and Loeys-Dietz syndromes. Int Heart J. 2016;57(3):271–7.

    Article  CAS  Google Scholar 

  30. Hawinkels LJ, Garcia de Vinuesa A, Ten Dijke P. Activin receptor-like kinase 1 as a target for anti-angiogenesis therapy. Expert Opin Investig Drugs. 2013;22(11):1371–83.

    Article  CAS  Google Scholar 

  31. Kaplon H, Reichert JM. Antibodies to watch in 2018. MAbs. 2018;10(2):183–203.

    Article  CAS  Google Scholar 

  32. Long L, Ormiston ML, Yang X, Southwood M, Gräf S, Machado RD, et al. Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat Med. 2015;21(7):777–85.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK

    Julian Tristan Schwartze, Emma Louise Low & Angela Claire Bradshaw

Authors
  1. Julian Tristan Schwartze
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emma Louise Low
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angela Claire Bradshaw
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Angela Claire Bradshaw .

Editor information

Editors and Affiliations

  1. Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, UK

    Rhian M. Touyz

  2. Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, UK

    Christian Delles

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Schwartze, J.T., Low, E.L., Bradshaw, A.C. (2019). TGF-β in Vascular Pathobiology. In: Touyz, R., Delles, C. (eds) Textbook of Vascular Medicine. Springer, Cham. https://doi.org/10.1007/978-3-030-16481-2_13

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-16481-2_13

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-16480-5

  • Online ISBN: 978-3-030-16481-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation