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Review
. 2021 Mar 27;22(7):3471.
doi: 10.3390/ijms22073471.

Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology

Sala Bofarid  1 , Anna E Hosman  2 , Johannes J Mager  2 , Repke J Snijder  2 , Marco C Post  1   3
Affiliations
Review

Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology

Sala Bofarid et al. Int J Mol Sci. .

Abstract

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Molecular pathophysiology of hereditary hemorrhagic telangiectasia (HHT). Physiological signaling in endothelial cells occurs through ALK-1 and ALK-5. Signaling through ALK-1 results in the activation of the SMAD 1,5,8-CoSMAD4 pathway resulting in proliferation and migration of endothelial cells (ECs). ALK-1 (and indirectly endoglin) also inhibits ALK-5 signaling. ALK-5 signaling activates the SMAD 2,3-CoSMAD4 pathway which inhibits proliferation and migration of ECs and stimulate the stabilization of the vessels.
Figure 2
Figure 2
Schematic model of the targets of bevacizumab and tacrolimus. Bevacizumab binds VEGF signaling molecules that prevent (vascular endothelial growth factor) VEGF from binding effectively to the VEGFR2 receptor and as a result it reduces neoangiogenesis. Bevacizumab enhances the BMP9-ALK1-ENG-SMAD pathway and enhances ENG and ALK1 expression.
See this image and copyright information in PMC

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