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Review

Hereditary Haemorrhagic Telangiectasia, an Inherited Vascular Disorder in Need of Improved Evidence-Based Pharmaceutical Interventions

1
Department of Infection, Immunity & Cardiovascular Disease, Medical School, University of Sheffield, Sheffield S10 2RX, UK
2
Biosciences Institute, Centre for Life, Newcastle University, Newcastle NE1 3BZ, UK
*
Author to whom correspondence should be addressed.
Academic Editor: Rosemary J. Akhurst
Genes 2021, 12(2), 174; https://doi.org/10.3390/genes12020174
Received: 4 December 2020 / Revised: 11 January 2021 / Accepted: 20 January 2021 / Published: 27 January 2021
(This article belongs to the Special Issue Genetic Disorders of the TGFβ Signaling Family)
Hereditary haemorrhagic telangiectasia (HHT) is characterised by arteriovenous malformations (AVMs). These vascular abnormalities form when arteries and veins directly connect, bypassing the local capillary system. Large AVMs may occur in the lungs, liver and brain, increasing the risk of morbidity and mortality. Smaller AVMs, known as telangiectases, are prevalent on the skin and mucosal lining of the nose, mouth and gastrointestinal tract and are prone to haemorrhage. HHT is primarily associated with a reduction in endoglin (ENG) or ACVRL1 activity due to loss-of-function mutations. ENG and ACVRL1 transmembrane receptors are expressed on endothelial cells (ECs) and bind to circulating ligands BMP9 and BMP10 with high affinity. Ligand binding to the receptor complex leads to activation of the SMAD1/5/8 signalling pathway to regulate downstream gene expression. Various genetic animal models demonstrate that disruption of this pathway in ECs results in AVMs. The vascular abnormalities underlying AVM formation result from abnormal EC responses to angiogenic and haemodynamic cues, and include increased proliferation, reduced migration against the direction of blood flow and an increased EC footprint. There is growing evidence that targeting VEGF signalling has beneficial outcomes in HHT patients and in animal models of this disease. The anti-VEGF inhibitor bevacizumab reduces epistaxis and has a normalising effect on high cardiac output in HHT patients with hepatic AVMs. Blocking VEGF signalling also reduces vascular malformations in mouse models of HHT1 and HHT2. However, VEGF signalling is complex and drives numerous downstream pathways, and it is not yet clear which pathway (or combination of pathways) is critical to target. This review will consider the recent evidence gained from HHT clinical and preclinical studies that are increasing our understanding of HHT pathobiology and informing therapeutic strategies. View Full-Text
Keywords: BMP9/10; ENG; ACVRL1; VEGF; angiogenesis; arteriovenous malformation BMP9/10; ENG; ACVRL1; VEGF; angiogenesis; arteriovenous malformation
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MDPI and ACS Style

Snodgrass, R.O.; Chico, T.J.A.; Arthur, H.M. Hereditary Haemorrhagic Telangiectasia, an Inherited Vascular Disorder in Need of Improved Evidence-Based Pharmaceutical Interventions. Genes 2021, 12, 174. https://doi.org/10.3390/genes12020174

AMA Style

Snodgrass RO, Chico TJA, Arthur HM. Hereditary Haemorrhagic Telangiectasia, an Inherited Vascular Disorder in Need of Improved Evidence-Based Pharmaceutical Interventions. Genes. 2021; 12(2):174. https://doi.org/10.3390/genes12020174

Chicago/Turabian Style

Snodgrass, Ryan O., Timothy J.A. Chico, and Helen M. Arthur 2021. "Hereditary Haemorrhagic Telangiectasia, an Inherited Vascular Disorder in Need of Improved Evidence-Based Pharmaceutical Interventions" Genes 12, no. 2: 174. https://doi.org/10.3390/genes12020174

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