Niu Gengming, Ye Taiyang, Qin Liuliang, Bourbon Pierre M, Chang Cheng, Zhao Shengqiang, Li Yan, Zhou Lei, Cui Pengfei, Rabinovitz Issac, Mercurio Arthur M, Zhao Dezheng, Zeng Huiyan
Center for Vascular Biology Research and Division of Molecular and Vascular Biology, Department of Medicine and Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China;
Center for Vascular Biology Research and Division of Molecular and Vascular Biology, Department of Medicine and Department of Obstetrics & Gynecology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, People's Republic of China;
FASEB J. 2015 Jan;29(1):131-40. doi: 10.1096/fj.14-257550. Epub 2014 Oct 17.
Tissue repair/wound healing, in which angiogenesis plays an important role, is a critical step in many diseases including chronic wound, myocardial infarction, stroke, cancer, and inflammation. Recently, we were the first to report that orphan nuclear receptor TR3/Nur77 is a critical mediator of angiogenesis and its associated microvessel permeability. Tumor growth and angiogenesis induced by VEGF-A, histamine, and serotonin are almost completely inhibited in Nur77 knockout mice. However, it is not known whether TR3/Nur77 plays any roles in wound healing. In these studies, skin wound-healing assay was performed in 3 types of genetically modified mice having various Nur77 activities. We found that ectopic induction of Nur77 in endothelial cells of mice is sufficient to improve skin wound healing. Although skin wound healing in Nur77 knockout mice is comparable to the wild-type control mice, the process is significantly delayed in the EC-Nur77-DN mice, in which a dominant negative Nur77 mutant is inducibly and specifically expressed in mouse endothelial cells. By a loss-of-function assay, we elucidate a novel feed-forward signaling pathway, integrin β4 → PI3K → Akt → FAK, by which TR3 mediates HUVEC migration. Furthermore, TR3/Nur77 regulates the expression of integrin β4 by targeting its promoter activity. In conclusion, expression of TR3/Nur77 improves wound healing by targeting integrin β4. TR3/Nur77 is a potential candidate for proangiogenic therapy. The results further suggest that TR3/Nur77 is required for pathologic angiogenesis but not for developmental/physiologic angiogenesis and that Nur77 and its family members play a redundant role in normal skin wound healing.
组织修复/伤口愈合是包括慢性伤口、心肌梗死、中风、癌症和炎症在内的许多疾病中的关键步骤，其中血管生成起着重要作用。最近，我们首次报道孤儿核受体TR3/Nur77是血管生成及其相关微血管通透性的关键介质。在Nur77基因敲除小鼠中，VEGF-A、组胺和5-羟色胺诱导的肿瘤生长和血管生成几乎完全受到抑制。然而，尚不清楚TR3/Nur77在伤口愈合中是否发挥任何作用。在这些研究中，我们在3种具有不同Nur77活性的基因改造小鼠中进行了皮肤伤口愈合试验。我们发现，在小鼠内皮细胞中异位诱导Nur77足以改善皮肤伤口愈合。虽然Nur77基因敲除小鼠的皮肤伤口愈合与野生型对照小鼠相当，但在EC-Nur77-DN小鼠中，这一过程明显延迟，在该小鼠中，显性负性Nur77突变体在小鼠内皮细胞中可诱导且特异性表达。通过功能丧失试验，我们阐明了一条新的前馈信号通路，即整合素β4→PI3K→Akt→FAK，TR3通过该通路介导人脐静脉内皮细胞迁移。此外，TR3/Nur77通过靶向整合素β4的启动子活性来调节其表达。总之，TR3/Nur77的表达通过靶向整合素β4来改善伤口愈合。TR3/Nur77是促血管生成治疗的潜在候选者。结果进一步表明，TR3/Nur77是病理性血管生成所必需的，但不是发育性/生理性血管生成所必需的，并且Nur77及其家族成员在正常皮肤伤口愈合中发挥冗余作用。
