An update on preclinical models of hereditary haemorrhagic telangiectasia: Insights into disease mechanisms.
An update on preclinical models of hereditary haemorrhagic telangiectasia: Insights into disease mechanisms.
复制标题
遗传性出血性毛细血管扩张的临床前模型的最新进展：对疾病机制的见解。
DOI：
10.3389/fmed.2022.973964
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发表时间：
2022
影响因子：
3.9
通讯作者：
中科院分区：
文献类型：
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内皮糖蛋白 (ENG) 在内皮细胞 (EC) 表面表达，有效结合循环 BMP9 和 BMP10 配体，启动激活素 A 受体样 1 (ALK1) 蛋白信号传导，从而保护血管结构。 ENG 或 ALK1 突变杂合子患者会出现称为遗传性出血性毛细血管扩张症 (HHT) 的血管疾病。许多患有这种疾病的患者患有贫血，并且中风和高输出量心力衰竭的风险也增加。最近使用 HHT 动物模型的研究揭示了导致这种疾病的细胞和分子机制的新见解。 EC 中 ENG (HHT1) 或 ALK1 (HHT2) 基因的缺失会导致发育中血管的动静脉连接异常或畸形 (AVM)。 EC 特异性缺失 SMAD1 和 5 或 EC 缺失 SMAD4 后会出现类似的表型。综上所述，这些数据表明 BMP9/10-ENG-ALK1-SMAD1/5-SMAD4 通路在保护脉管系统免受 AVM 侵害方面发挥着重要作用。 ECs 响应剪切应力而改变方向迁移和 EC 增殖增加现在被认为是驱动 AVM 形成的关键因素。 ENG/ALK1 信号通路的破坏也会影响 EC 对血管内皮生长因子 (VEGF) 的反应以及 EC 和血管平滑肌细胞之间的串扰。令人惊讶的是，HHT 中的血管病变既是局部的又是组织特异性的。越来越多的证据表明，第二次基因打击对于产生双等位基因突变的重要性，而这种体细胞突变的散发性可以解释血管病变的局部形成。此外，AVM 形成的不同促血管生成驱动因素可能在患者的生命过程中发挥作用。例如，炎症是产后血管重塑的关键驱动因素，并且可能是 HHT 疾病的重要驱动因素。目前丰富的 HHT 临床前模型增加了对 AVM 发展的了解，并揭示了治疗 AVM 的新治疗方法，并构成了本综述的主题。
Endoglin (ENG) is expressed on the surface of endothelial cells (ECs) where it efficiently binds circulating BMP9 and BMP10 ligands to initiate activin A receptor like type 1 (ALK1) protein signalling to protect the vascular architecture. Patients heterozygous for ENG or ALK1 mutations develop the vascular disorder known as hereditary haemorrhagic telangiectasia (HHT). Many patients with this disorder suffer from anaemia, and are also at increased risk of stroke and high output heart failure. Recent work using animal models of HHT has revealed new insights into cellular and molecular mechanisms causing this disease. Loss of the ENG (HHT1) or ALK1 (HHT2) gene in ECs leads to aberrant arteriovenous connections or malformations (AVMs) in developing blood vessels. Similar phenotypes develop following combined EC specific loss of SMAD1 and 5, or EC loss of SMAD4. Taken together these data point to the essential role of the BMP9/10-ENG-ALK1-SMAD1/5-SMAD4 pathway in protecting the vasculature from AVMs. Altered directional migration of ECs in response to shear stress and increased EC proliferation are now recognised as critical factors driving AVM formation. Disruption of the ENG/ALK1 signalling pathway also affects EC responses to vascular endothelial growth factor (VEGF) and crosstalk between ECs and vascular smooth muscle cells. It is striking that the vascular lesions in HHT are both localised and tissue specific. Increasing evidence points to the importance of a second genetic hit to generate biallelic mutations, and the sporadic nature of such somatic mutations would explain the localised formation of vascular lesions. In addition, different pro-angiogenic drivers of AVM formation are likely to be at play during the patient’s life course. For example, inflammation is a key driver of vessel remodelling in postnatal life, and may turn out to be an important driver of HHT disease. The current wealth of preclinical models of HHT has led to increased understanding of AVM development and revealed new therapeutic approaches to treat AVMs, and form the topic of this review.