Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology

Int J Mol Sci. 2021 Mar 27;22(7):3471. doi: 10.3390/ijms22073471.


In this review, we discuss the role of transforming growth factor-beta (TGF-β) in the development of pulmonary vascular disease (PVD), both pulmonary arteriovenous malformations (AVM) and pulmonary hypertension (PH), in hereditary hemorrhagic telangiectasia (HHT). HHT or Rendu-Osler-Weber disease is an autosomal dominant genetic disorder with an estimated prevalence of 1 in 5000 persons and characterized by epistaxis, telangiectasia and AVMs in more than 80% of cases, HHT is caused by a mutation in the ENG gene on chromosome 9 encoding for the protein endoglin or activin receptor-like kinase 1 (ACVRL1) gene on chromosome 12 encoding for the protein ALK-1, resulting in HHT type 1 or HHT type 2, respectively. A third disease-causing mutation has been found in the SMAD-4 gene, causing a combination of HHT and juvenile polyposis coli. All three genes play a role in the TGF-β signaling pathway that is essential in angiogenesis where it plays a pivotal role in neoangiogenesis, vessel maturation and stabilization. PH is characterized by elevated mean pulmonary arterial pressure caused by a variety of different underlying pathologies. HHT carries an additional increased risk of PH because of high cardiac output as a result of anemia and shunting through hepatic AVMs, or development of pulmonary arterial hypertension due to interference of the TGF-β pathway. HHT in combination with PH is associated with a worse prognosis due to right-sided cardiac failure. The treatment of PVD in HHT includes medical or interventional therapy.

Keywords: HHT; endoglin; pulmonary vascular disease.

Publication types

  • Review

MeSH terms

  • Activin Receptors, Type II / metabolism
  • Animals
  • Arteriovenous Malformations / complications
  • Arteriovenous Malformations / genetics
  • Endoglin / metabolism
  • Humans
  • Hypertension, Pulmonary / complications
  • Hypertension, Pulmonary / genetics
  • Lung Diseases / complications*
  • Lung Diseases / genetics
  • Mutation
  • Risk
  • Signal Transduction
  • Telangiectasia, Hereditary Hemorrhagic / complications*
  • Telangiectasia, Hereditary Hemorrhagic / genetics
  • Transforming Growth Factor beta / metabolism
  • Vascular Diseases / complications*
  • Vascular Diseases / genetics


  • ENG protein, human
  • Endoglin
  • Transforming Growth Factor beta
  • ACVRL1 protein, human
  • Activin Receptors, Type II