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

Abstract

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.

Identification of Exosomal MicroRNA Signature by Liquid Biopsy in Hereditary Hemorrhagic Telangiectasia Patients

“…Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber syndrome is a vascular dysplasia with autosomal dominant traits characterized by recurrent and spontaneous nose bleeds (epistaxis), mucocutaneous telangiectases, and arteriovenous malformations (AVM) in the internal organs, including the lungs, liver, and brain [1]. Mutations in the encoding gene for the transforming growth factor (TGF)-β receptors endoglin (ENG) and Activin A receptor type II-like 1, ALK1 (ACVRL1), lead to HHT type 1 (MIM #187300) and type 2 (MIM #600376), respectively [2].…”

“…Mutations in the encoding gene for the transforming growth factor (TGF)-β receptors endoglin (ENG) and Activin A receptor type II-like 1, ALK1 (ACVRL1), lead to HHT type 1 (MIM #187300) and type 2 (MIM #600376), respectively [2]. Both types account for the majority of the genetically diagnosed HHT population (85% approximately), although recent reports point to mutations in other components of the TGF-β signaling pathway, such as SMAD4 (MIM #175050) and BMP9 (GDF2) (MIM #615506), in a reduced HHT population [1]. In any case, HHT is a rare disease with an estimated prevalence around 1/8000.…”

PTPN14, a modifier of HHT, protects SMAD4 from ubiquitination and turnover to potentiate BMP9 signaling in endothelial cells

“…Thalidomide and pomalidomide, drugs that target components of the ubiquitylation machinery, are already of use or in clinical trial for HHT therapy 56 , and this class of IMiD drugs may affect both PTPN14/SMAD and PTPN14/YAP/TAZ ubiquitylation and turnover. Future design of more specific drugs with fewer side effects, would benefit from knowledge of the interactions that regulate stability of PTPN14, (which was not certified by peer review) is the author/funder.…”

Myostatin/Activin-A Signaling in the Vessel Wall and Vascular Calcification

“…Considering the negative effects of Mstn on muscle growth, clinical studies have been performed mainly to evaluate whether the block of Mstn signaling might improve muscle mass and performance status in patients with sarcopenia and muscular dystrophy [117], whereas no data are available on the vascular effects of Mstn inhibition. It is interesting that one of these studies, a phase 2 trial of ACE-031 in boys with Duchenne's muscle dystrophy, was prematurely terminated [118] following the occurrence of signs observed in patients with hereditary hemorrhagic telangiectasia (HHT), a disease caused by mutations in ALK-1, which blunts TGFβ receptor signaling in endothelial cells [119]. In addition, a more recently developed ligand trap, ActRIIA-Fc, blunts myostatin, activin, and GDF11 actions in endothelial cells, as well as arteriolar remodeling, while promoting vessel apoptosis in animal models of PAH [120].…”