Department of Internal Medicine (Nephrology), Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Physics for Medicine, ESPCI, INSERM U1273, CNRS, Paris, France.
Adv Exp Med Biol. 2019;1147:215-246. doi: 10.1007/978-3-030-16908-4_10.
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by multi-systemic vascular dysplasia affecting 1 in 5000 people worldwide. Individuals with HHT suffer from many complications including nose and gastrointestinal bleeding, anemia, iron deficiency, stroke, abscess, and high-output heart failure. Identification of the causative gene mutations and the generation of animal models have revealed that decreased transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signaling and increased vascular endothelial growth factor (VEGF) signaling activity in endothelial cells are responsible for the development of the vascular malformations in HHT. Perturbations in these key pathways are thought to lead to endothelial cell activation resulting in mural cell disengagement from the endothelium. This initial instability state causes the blood vessels to response inadequately when they are exposed to angiogenic triggers resulting in excessive blood vessel growth and the formation of vascular abnormalities that are prone to bleeding. Drugs promoting blood vessel stability have been reported as effective in preclinical models and in clinical trials indicating possible interventional targets based on a normalization approach for treating HHT. Here, we will review how disturbed TGF-β and VEGF signaling relates to blood vessel destabilization and HHT development and will discuss therapeutic opportunities based on the concept of vessel normalization to treat HHT.
遗传性出血性毛细血管扩张症（HHT）是一种遗传疾病，其特征为多系统血管发育不良，影响全球每 5000 人中就有 1 人。患有 HHT 的个体易患多种并发症，包括鼻出血和胃肠道出血、贫血、缺铁、中风、脓肿和高输出量心力衰竭。致病基因突变的鉴定和动物模型的产生揭示了内皮细胞中转化生长因子-β（TGF-β）/骨形态发生蛋白（BMP）信号的减少和血管内皮生长因子（VEGF）信号活性的增加是导致 HHT 血管畸形发展的原因。这些关键途径的紊乱被认为会导致内皮细胞激活，从而导致壁细胞与内皮细胞分离。这种初始不稳定状态导致血管在暴露于血管生成触发因素时反应不足，导致血管过度生长和形成易出血的血管异常。促进血管稳定性的药物已在临床前模型和临床试验中显示出有效性，表明基于血管正常化的治疗方法可能是治疗 HHT 的干预靶点。在这里，我们将回顾 TGF-β和 VEGF 信号的紊乱如何与血管不稳定和 HHT 的发展相关，并将根据血管正常化的概念讨论治疗 HHT 的治疗机会。
