title: Orphan nuclear receptor TR3/Nur77 improves wound healing by upregulating the expression of integrin β4.
abstract: 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.
authors.affiliation: 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;
authors.forename: Gengming
authors.initials: G
authors.lastname: Niu
authors.affiliation: 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;
authors.forename: Taiyang
authors.initials: T
authors.lastname: Ye
authors.affiliation: Department of Pathology.
authors.forename: Liuliang
authors.initials: L
authors.lastname: Qin
authors.affiliation: Department of Pathology.
authors.forename: Pierre M
authors.initials: PM
authors.lastname: Bourbon
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA;
authors.forename: Cheng
authors.initials: C
authors.lastname: Chang
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Biology, Department of Medicine and Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University, Ji-nan, People's Republic of China;
authors.forename: Shengqiang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Biology, Department of Medicine and Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University, Ji-nan, People's Republic of China;
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Biology, Department of Medicine and Departments of Hepatobiliary Surgery and General Surgery, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, People's Republic of China;
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Biology, Department of Medicine and Department of General Surgery, Pancreatic Disease Institute, Union Hospital, Huazhong University of Science & Technology (HUST), Wuhan, People's Republic of China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Cui
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Biology, Department of Medicine and Department of Pathology.
authors.forename: Issac
authors.initials: I
authors.lastname: Rabinovitz
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA;
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Mercurio
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Biology, Department of Medicine and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Dezheng
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Biology, Department of Medicine and hzeng@caregroup.harvard.edu.
authors.forename: Huiyan
authors.initials: H
authors.lastname: Zeng
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D039663:Integrin beta4 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D012867:Skin / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
chemical_list: D039663:Integrin beta4; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D034741:RNA, Small Interfering
keywords: VEGF; angiogenesis