Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia
Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia
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DOI：
10.1038/nm.2131
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发表时间：
2010-04-01
期刊：
影响因子：
82.9
通讯作者：
Mummery, Christine L.
中科院分区：
文献类型：
--
作者：
Lebrin, Franck;Srun, Samly;Mummery, Christine L.
遗传性出血性毛细血管扩张症（HHT）是一种以血管畸形为特征的遗传性疾病。许多受影响的人会出现反复流鼻血，这会严重影响他们的生活质量，并且临床上难以治疗。我们在此报告，沙利度胺治疗降低了一小群 HHT 测试受试者中大多数鼻出血（鼻出血）的严重程度和频率。由于出血减少和血管稳定性增强，接受治疗的个体血液中的血红蛋白水平上升。在 Eng 基因（编码内皮糖蛋白）杂合子小鼠（一种 HHT 实验模型）中，沙利度胺治疗刺激了壁细胞覆盖，从而挽救了血管壁缺陷。沙利度胺治疗增加内皮细胞中血小板衍生生长因子-B (PDGF-B) 的表达并刺激壁细胞活化。沙利度胺治疗的效果通过药理或遗传干扰从内皮细胞到周细胞的 PDGF 信号而部分逆转。对接受或未接受沙利度胺治疗的 HHT 个体进行的鼻上皮活检表明，类似的机制可以解释沙利度胺治疗对人类的影响。我们的研究结果证明沙利度胺具有诱导血管成熟的能力，这可能可作为治疗血管畸形的治疗策略。
Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder characterized by vascular malformations. Many affected individuals develop recurrent nosebleeds, which can severely affect their quality of life and are clinically difficult to treat. We report here that treatment with thalidomide reduced the severity and frequency of nosebleeds (epistaxis) in the majority of a small group of subjects with HHT tested. The blood hemoglobin levels of the treated individuals rose as a result of reduced hemorrhage and enhanced blood vessel stabilization. In mice heterozygous for a null mutation in the Eng gene (encoding endoglin), an experimental model of HHT, thalidomide treatment stimulated mural cell coverage and thus rescued vessel wall defects. Thalidomide treatment increased platelet-derived growth factor-B (PDGF-B) expression in endothelial cells and stimulated mural cell activation. The effects of thalidomide treatment were partially reversed by pharmacological or genetic interference with PDGF signaling from endothelial cells to pericytes. Biopsies of nasal epithelium from individuals with HHT treated or not with thalidomide showed that similar mechanisms may explain the effects of thalidomide treatment in humans. Our findings demonstrate the ability of thalidomide to induce vessel maturation, which may be useful as a therapeutic strategy for the treatment of vascular malformations.