BACKGROUND Small bowel vascular malformation disease (SBVM) is the most common cause of obscure gastrointestinal bleeding (OGIB). Several studies suggested that EGFL6 was able to promote the growth of tumor endothelial cells by forming tumor vessels. To date, it remains unclear how EGFL6 promotes pathological angiogenesis in SBVM and whether EGFL6 is a target of thalidomide. METHODS We took advantage of SBVM plasma and tissue samples and compared the expression of EGFL6 between SBVM patients and healthy people via ELISA and Immunohistochemistry. We elucidated the underlying function of EGFL6 in SBVM in vitro and by generating a zebrafish model that overexpresses EGFL6, The cycloheximide (CHX)-chase experiment and CoIP assays were conducted to demonstrate that thalidomide can promote the degradation of EGFL6 by targeting CRBN. RESULTS The analysis of SBVM plasma and tissue samples revealed that EGFL6 was overexpressed in the patients compared to healthy people. Using in vitro and in vivo assays, we demonstrated that an EMT pathway triggered by the EGFL6/PAX6 axis is involved in the pathogenesis of SBVM. Furthermore, through in vitro and in vivo assays, we elucidated that thalidomide can function as anti-angiogenesis medicine through the regulation of EGFL6 in a proteasome-dependent manner. Finally, we found that CRBN can mediate the effect of thalidomide on EGFL6 expression and that the CRBN protein interacts with EGFL6 via a Lon N-terminal peptide. CONCLUSION Our findings revealed a key role for EGFL6 in SBVM pathogenesis and provided a mechanism explaining why thalidomide can cure small bowel bleeding resulting from SBVM.

中文翻译：

---

沙利度胺以 EGFL6 为靶点，抑制小肠血管畸形中 EGFL6/PAX6 轴驱动的血管生成。


背景小肠血管畸形疾病（SBVM）是不明原因胃肠道出血（OGIB）的最常见原因。多项研究表明EGFL6能够通过形成肿瘤血管来促进肿瘤内皮细胞的生长。迄今为止，尚不清楚 EGFL6 如何促进 SBVM 的病理性血管生成以及 EGFL6 是否是沙利度胺的靶点。方法我们利用 SBVM 血浆和组织样本，通过 ELISA 和免疫组织化学比较 SBVM 患者和健康人之间 EGFL6 的表达。我们在体外阐明了 SBVM 中 EGFL6 的基本功能，并通过生成过表达 EGFL6 的斑马鱼模型，进行了放线菌酮 (CHX) 追踪实验和 CoIP 测定，以证明沙利度胺可以通过靶向 CRBN 促进 EGFL6 的降解。结果 SBVM 血浆和组织样本的分析显示，与健康人相比，患者中 EGFL6 过度表达。通过体外和体内测定，我们证明由 EGFL6/PAX6 轴触发的 EMT 途径参与了 SBVM 的发病机制。此外，通过体外和体内试验，我们阐明沙利度胺可以通过蛋白酶体依赖性方式调节 EGFL6 作为抗血管生成药物。最后，我们发现CRBN可以介导沙利度胺对EGFL6表达的影响，并且CRBN蛋白通过Lon N端肽与EGFL6相互作用。结论 我们的研究结果揭示了 EGFL6 在 SBVM 发病机制中的关键作用，并提供了解释为什么沙利度胺可以治疗 SBVM 引起的小肠出血的机制。