Center for Vascular Biology Research and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Radiotherapy and Medical Oncology Department, Zhongnan Hospital, Wuhan University, Wuhan, PR China.
Center for Vascular Biology Research and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, PR China.
Microvasc Res. 2019 Jul;124:67-75. doi: 10.1016/j.mvr.2019.03.006. Epub 2019 Mar 28.
Pathological angiogenesis is a hallmark of many diseases. Previously, we reported that orphan nuclear receptor TR3/Nur77 was a critical mediator of angiogenesis to regulate tumor growth and skin wound healing via regulating the expression of the junctional proteins and integrins. However, the molecular mechanism, by which TR3/Nur77 regulates angiogenesis is not completely understood. Here, we were the first to find that TR3/Nur77, via its various amino acid fragments, regulated the expression of DLL4 and Jagged 1 in cultured endothelial cells. DLL4 and Jagged1 mediated TR3/Nur77-induced angiogenic responses and signaling molecules, but not the expression of integrins. Instead, integrins regulated the expressions of DLL4 and Jagged1 induced by TR3/Nur77. Further, DLL4, Jagged1 and integrins α1, α2, β3 and β5 were regulated by TR3/Nur77 in animal sepsis models of lipopolysaccharide (LPS)-induced endotoxemia, and cecal ligation and puncture (CLP), in which, TR3/Nur77 expression was significantly and tranciently increased. Mouse survival rates were greatly increased in Nur77 knockout mice bearing both CLP and LPS models. The results elucidated a novel axis of VEGF/histamine ➔ TR3/Nur77 ➔ integrins ➔ DLL4/Jagged1 in angiogenesis, and demonstrated that TR3/Nur77 was an excellent target for sepsis. These studies supported our previous findings that TR3/Nur77 was an excellent therapeutic target, and further our understanding of the molecular mechanism, by which TR3/Nur77 regulated angiogenesis.
病理性血管生成是许多疾病的标志。以前，我们报道过孤儿核受体 TR3/Nur77 是血管生成的关键介质，通过调节连接蛋白和整合素的表达来调节肿瘤生长和皮肤伤口愈合。然而，TR3/Nur77 调节血管生成的分子机制尚不完全清楚。在这里，我们首次发现 TR3/Nur77 通过其各种氨基酸片段调节培养的内皮细胞中 DLL4 和 Jagged1 的表达。DLL4 和 Jagged1 介导 TR3/Nur77 诱导的血管生成反应和信号分子，但不调节整合素的表达。相反，整合素调节由 TR3/Nur77 诱导的 DLL4 和 Jagged1 的表达。此外，在脂多糖（LPS）诱导的内毒素血症和盲肠结扎和穿刺（CLP）的动物脓毒症模型中，TR3/Nur77 调节 DLL4、Jagged1 以及整合素 α1、α2、β3 和β5 的表达，其中 TR3/Nur77 的表达显著且短暂增加。在同时患有 CLP 和 LPS 模型的 Nur77 敲除小鼠中，小鼠的存活率大大提高。这些结果阐明了血管生成中 VEGF/组胺 ➔ TR3/Nur77 ➔ 整合素 ➔ DLL4/Jagged1 的新轴，并表明 TR3/Nur77 是脓毒症的一个极好靶点。这些研究支持了我们之前的发现，即 TR3/Nur77 是一个极好的治疗靶点，并进一步加深了我们对 TR3/Nur77 调节血管生成的分子机制的理解。
