Department of Infection, Immunity & Cardiovascular Disease, Medical School, University of Sheffield, Sheffield S10 2RX, UK.
Biosciences Institute, Centre for Life, Newcastle University, Newcastle NE1 3BZ, UK.
Genes (Basel). 2021 Jan 27;12(2):174. doi: 10.3390/genes12020174.
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.
遗传性出血性毛细血管扩张症（HHT）的特征是动静脉畸形（AVM）。当动脉和静脉直接连接，绕过局部毛细血管系统时，这些血管异常就会形成。大的 AVM 可能发生在肺部、肝脏和大脑，增加发病率和死亡率。较小的 AVM，称为毛细血管扩张症，在鼻子、口腔和胃肠道的皮肤和黏膜衬里上很常见，容易出血。HHT 主要与内皮糖蛋白（ENG）或 ACVRL1 活性降低有关，这是由于功能丧失突变引起的。ENG 和 ACVRL1 跨膜受体在血管内皮细胞（EC）上表达，并与循环配体 BMP9 和 BMP10 以高亲和力结合。配体与受体复合物的结合导致 SMAD1/5/8 信号通路的激活，以调节下游基因表达。各种遗传动物模型表明，EC 中该途径的破坏导致 AVM 的形成。AVM 形成下的血管异常是由于 EC 对血管生成和血液动力学线索的异常反应引起的，包括增殖增加、对血流方向的迁移减少以及 EC 足迹增加。越来越多的证据表明，靶向 VEGF 信号在 HHT 患者和该疾病的动物模型中具有有益的结果。抗 VEGF 抑制剂贝伐单抗可减少鼻出血，并对 HHT 伴有肝 AVM 的患者的高心输出量产生正常化作用。阻断 VEGF 信号也可减少 HHT1 和 HHT2 小鼠模型中的血管畸形。然而，VEGF 信号是复杂的，可驱动许多下游途径，目前尚不清楚哪个途径（或途径组合）是关键的靶向目标。本综述将考虑从 HHT 临床和临床前研究中获得的最新证据，这些证据增加了我们对 HHT 病理生物学的理解，并为治疗策略提供了信息。
