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.
Highlights
Hereditary Haemorrhagic Telangiectasia (HHT) is an inherited vascular disorder affecting up to 1 in 5000 people
This review will focus on the two major patient groups, HHT1 and HHT2 that are caused by loss-of-function (LOF) mutations in ENG and ACVRL1, respectively
HHT1 and HHT2 patients develop very similar clinical symptoms that result from sporadic vascular malformations, with clinical diagnosis based on the “Curacao criteria”
Summary
Hereditary Haemorrhagic Telangiectasia (HHT) is an inherited vascular disorder affecting up to 1 in 5000 people. ENG and ACVRL1 proteins are expressed on the endothelial cell (EC) surface They are found in other cell types, for example, in fibroblasts, but overwhelming evidence from preclinical studies points to the critical nature of their endothelial role in protecting against vascular malformations in HHT [6]. ENG protein is released from the complex following recruitment of the type II receptor (either BMPR2 or ACTRIIB or ACTRIIA) which phosphorylates ACVRL1 kinase to activate and propagate the signalling cascade via activation of transcription factors. Moving downstream of the signalling pathway, the critical importance of the canonical SMAD1/5/8 pathway in protecting ECs against vascular malformations is shown by the HHT-like phenotype in SMAD4 LOF mutation patients [2], and by the retinal AVMs that develop in neonatal mice with endothelial loss of either SMAD4 or SMAD1/5 [24,25].
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