Angiopoietin-1 and Vascular Endothelial Growth Factor Regulation of Leukocyte Adhesion to Endothelial Cells Role of Nuclear Receptor-77

作者：Ismail Hodan; Mofarrahi Mahroo; Echavarria Raquel; Harel Sharon; Verdin Eric; Lim Hyung W; Jin Zheng Gen; Sun Jianxin; Zeng Huiyan; Hussain Sabah N A^*

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2012, 32(7): 1707-1716.

DOI：10.1161/ATVBAHA.112.251546

• angiopoietin-1
• endothelial cells
• inflammation
• leukocyte adhesion
• nuclear receptor-77
• vascular endothelial growth factor

Objective-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. %26lt;br%26gt;Methods and Results-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 %26gt;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. %26lt;br%26gt;Conclusion-Nur77 promotes anti-inflammatory effects of Ang-1, and functions as a negative feedback inhibitor of VEGF-induced EC activation. (Arterioscler Thromb Vasc Biol. 2012;32:1707-1716.)

• 出版日期2012-7