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 alpha 1, alpha 2, beta 3 and beta 5 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.
[1]Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Boston, MA 02215 USA;
[2]Beth Israel Deaconess Med Ctr, Dept Med, Div Gastroenterol, Boston, MA 02215 USA;
[3]Harvard Med Sch, Boston, MA 02115 USA;
[4]Wuhan Univ, Zhongnan Hosp, Radiotherapy & Med Oncol Dept, Wuhan, Hubei, Peoples R China;
[5]Shandong Univ, Dept Gastroenterol, Shandong Prov Hosp, Jinan 250021, Shandong, Peoples R China;
[6]Fudan Univ, Huashan Hosp, Dept Gen Surg, Shanghai 200040, Peoples R China;
[7]Huazhong Univ Sci & Technol, Tongji Med Coll, Dept Surg Breast & Thyroid, Union Hosp, Wuhan 430022, Hubei, Peoples R China;
[8]Shanghai Jiao Tong Univ, Renji Hosp, Dept Obstet & Gynecol, Sch Med, Shanghai 200127, Peoples R China
(8.0+极速模式)