Expression and Function of TR3/nur77 in angiogenesis

描述（申请人提供）：病理性血管生成是癌症和各种缺血性和炎症性疾病的标志。VPF/VEGF因其对血管内皮的效力和选择性而成为最重要的血管生成因子。VPF/VEGF不仅参与血管生成的几个步骤，而且是迄今为止唯一发现的使微血管对循环大分子高渗透的有效因子。VPF/VEGF广泛重编程基因表达，刺激内皮细胞迁移和分裂，保护内皮细胞免于凋亡和衰老。为了分析VPF/VEGF诱导的基因，用VPF/VEGF刺激培养的HUVEC获得的RNA进行DNA芯片检测。核受体TR3是一种转录因子，是高度上调的基因之一。此外，TR3的小鼠同源物Nur77在VPF/VEGF处理的小鼠肠系膜中上调，其中只有EC表达VPF/VEGF受体。进一步的实验表明，TR3是VPF/ vegf刺激的HUVEC增殖所必需的。然而，TR3义的过表达会抑制VPF/VEGF刺激的HUVEC迁移，但通过反义途径阻断内源性TR3的表达会在缺乏VPF/VEGF的情况下触发HUVEC迁移。众所周知，TR3/nur77在发育、体内平衡和疾病中起着至关重要的作用。然而，TR3/nur77是否在血管生成中起作用尚不清楚。

DESCRIPTION (provided by applicant): Pathological angiogenesis is a hallmark of cancer and various ischaemic and inflammatory diseases. VPF/VEGF is the most important angiogenic factor because of its potency and selectivity for vascular endothelium. VPF/VEGF is not only involved in several steps of angiogenesis, but also the only potent factor rendering microvessels hyperpermeable to circulating macromolecules identified so far. VPF/VEGF extensively reprograms gene expression, stimulates endothelial cell migration and division, and protects endothelial cells from apoptosis and senescence. In order to profile the genes induced by VPF/VEGF, DNA microarray assay was conducted with RNA obtained from cultured HUVEC stimulated with VPF/VEGF. Nuclear receptor TR3, a transcription factor, is one of the highly upregulated genes. In addition, Nur77, the mouse homologue of TR3, is upregulated in the mesentery of VPF/VEGF-treated mouse, where only EC express VPF/VEGF receptors. Further experiments indicated that TR3 is required for VPF/VEGF-stimulated HUVEC proliferation. However, overexpression of sense TR3 inhibits VPF/VEGF-stimulated HUVEC migration, but blocking the expression of the endogenous TR3 by an antisense approach triggers HUVEC migration in the absence of VPF/VEGF. It is known that TR3/nur77 plays crucial roles in development, homeostasis and diseases. However, whether TR3/nur77 plays a role in angiogenesis is not known. The overall goal of this application is to study the function of the nuclear receptor TR3/nur77 in VPF/VEGF-induced angiogenesis and the signaling pathways that regulate VPF/VEGF-induced TR3 expression. The specific aims of this application are: (1) Investigate TR3/nur77 expression in the pathological angiogenesis induced by VPF/VEGF, tumors and wounding. (2) Determine the function of TR3/nur77 in angiogenesis. (3) Define the molecular mechanisms regulating TR3/Nur77 expression.