Angiopoietin-1 and vascular endothelial growth factor regulation of leukocyte adhesion to endothelial cells: role of nuclear receptor-77.
Angiopoietin-1 and vascular endothelial growth factor regulation of leukocyte adhesion to endothelial cells: role of nuclear receptor-77.
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DOI：
10.1161/atvbaha.112.251546
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发表时间：
2012-07
期刊：
影响因子：
--
通讯作者：
Hussain SN
中科院分区：
文献类型：
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作者：
Ismail H;Mofarrahi M;Echavarria R;Harel S;Verdin E;Lim HW;Jin ZG;Sun J;Zeng H;Hussain SN
血管内皮生长因子(VEGF)促进白细胞与内皮细胞(ECs)的黏附。血管生成素-1(Ang-1)抑制这种反应。核受体-77(Nur77)是一种促血管生成的核受体。在本研究中，我们观察了血管生成素-1和血管内皮生长因子对内皮细胞Nur77表达的影响，并探讨了其在血管紧张素-1/血管内皮生长因子介导的白细胞黏附中的作用。用实时定量聚合酶链式反应和免疫印迹法检测Nur77基因的表达。倒置显微镜下观察白细胞与内皮细胞的黏附情况。表达NUR77显性-负性形式的腺病毒、反义表达NUR77的逆转录病毒和小干扰RNA寡核苷酸可抑制NUR77的表达或活性。血管紧张素-1和血管内皮生长因子均可诱导Nur77的表达，其作用分别是前者的5倍和30倍。联合使用时，Ang-1可增强血管内皮生长因子诱导的Nur77的表达。Ang-1通过磷脂酰肌醇3-激酶和细胞外信号调节蛋白激酶1/2途径诱导Nur77。血管内皮生长因子通过蛋白激酶D/组蛋白脱乙酰酶7/肌细胞增强因子2和细胞外信号调节蛋白激酶1/2途径诱导Nur77的表达。血管内皮生长因子可诱导核因子-kappaB转录因子、血管细胞黏附分子-1和E-选择素的表达，促进白细胞与内皮细胞的黏附。Ang-1抑制这些反应。当Nur77的表达被干扰时，Ang-1的这种抑制作用消失，恢复了VEGF对黏附分子表达的诱导作用，并增加了白细胞与内皮细胞的黏附。Nur77促进Ang-1的抗炎作用，并作为血管内皮生长因子诱导的EC激活的负反馈抑制物发挥作用。
Vascular endothelial growth factor (VEGF) promotes leukocyte adhesion to endothelial cells (ECs). Angiopoietin-1 (Ang-1) inhibits this response. Nuclear receptor-77 (Nur77) is a proangiogenic nuclear receptor. In the present study, we assessed the influence of Ang-1 and VEGF on Nur77 expression in ECs, and evaluated its role in Ang-1/VEGF-mediated leukocyte adhesion. Expression of Nur77 was evaluated with real-time polymerase chain reaction and immunoblotting. Adhesion of leukocytes to ECs was monitored with inverted microscopy. Nur77 expression or activity was inhibited using adenoviruses expressing dominant-negative form of Nur77, retroviruses expressing Nur77 in the antisense direction, and small interfering RNA oligos. Both Ang-1 and VEGF induce Nur77 expression, by >5- and 30-fold, respectively. When combined, Ang-1 potentiates VEGF-induced Nur77 expression. Ang-1 induces Nur77 through the phosphoinositide 3-kinase and extracellular signal-regulated protein kinase 1/2 pathways. VEGF induces Nur77 expression through the protein kinase D/histone deacetylase 7/myocyte enhancer factor 2 and extracellular signal-regulated protein kinase 1/2 pathways. VEGF induces nuclear factor-kappaB transcription factor, vascular cell adhesion molecule-1, and E-selectin expressions, and promotes leukocyte adhesion to ECs. Ang-1 inhibits these responses. This inhibitory effect of Ang-1 disappears when Nur77 expression is disrupted, restoring the inductive effects of VEGF on adhesion molecule expression, and increased leukocyte adhesion to ECs. Nur77 promotes anti-inflammatory effects of Ang-1, and functions as a negative feedback inhibitor of VEGF-induced EC activation.