Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine (Nephrology), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Department of Mechanical Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8654, Japan.
Int J Mol Sci. 2021 Aug 19;22(16):8948. doi: 10.3390/ijms22168948.
Hereditary Hemorrhagic Telangiectasia type 1 (HHT1) is an autosomal dominant inherited disease characterized by arteriovenous malformations and hemorrhage. HHT1 is caused by mutations in , which encodes an ancillary receptor for Transforming Growth Factor-β/Bone Morphogenetic Protein-9 expressed in all vascular endothelial cells. Haploinsufficiency is widely accepted as the underlying mechanism for HHT1. However, it remains intriguing that only some, but not all, vascular beds are affected, as these causal gene mutations are present in vasculature throughout the body. Here, we have examined the endoglin expression levels in the blood vessels of multiple organs in mice and in humans. We found a positive correlation between low basal levels of endoglin and the general prevalence of clinical manifestations in selected organs. Endoglin was found to be particularly low in the skin, the earliest site of vascular lesions in HHT1, and even undetectable in the arteries and capillaries of heterozygous endoglin mice. Endoglin levels did not appear to be associated with organ-specific vascular functions. Instead, our data revealed a critical endoglin threshold compatible with the haploinsufficiency model, below which endothelial cells independent of their tissue of origin exhibited abnormal responses to Vascular Endothelial Growth Factor. Our results support the development of drugs promoting endoglin expression as potentially protective.
遗传性出血性毛细血管扩张症 1 型（HHT1）是一种常染色体显性遗传疾病，其特征为动静脉畸形和出血。HHT1 是由编码转化生长因子-β/骨形态发生蛋白-9 辅助受体的基因突变引起的，该基因在所有血管内皮细胞中表达。单倍不足被广泛认为是 HHT1 的潜在机制。然而，令人好奇的是，只有一些，而不是所有的血管床受到影响，因为这些因果基因突变存在于全身的脉管系统中。在这里，我们检查了多个器官的血管内皮蛋白在小鼠和人类中的表达水平。我们发现，基础水平低的内皮蛋白与选定器官临床表现的普遍发生率之间存在正相关。内皮蛋白在 HHT1 中血管病变最早发生的皮肤中尤其低，甚至在杂合子内皮蛋白小鼠的动脉和毛细血管中也无法检测到。内皮蛋白水平似乎与特定于器官的血管功能无关。相反，我们的数据揭示了一个与单倍不足模型兼容的关键内皮蛋白阈值，低于该阈值，无论其组织来源如何，内皮细胞对血管内皮生长因子的反应都异常。我们的研究结果支持开发促进内皮蛋白表达的药物作为潜在的保护剂。
