Adrenocorticotropin preferentially up-regulates angiopoietin 2 in the human fetal adrenal gland: Implications for coordinated adrenal organ growth and angiogenesis
Adrenocorticotropin preferentially up-regulates angiopoietin 2 in the human fetal adrenal gland: Implications for coordinated adrenal organ growth and angiogenesis
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DOI：
10.1210/jc.2005-2252
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发表时间：
2006-05-01
影响因子：
5.8
通讯作者：
Jaffe, RB
中科院分区：
文献类型：
--
作者：
Ishimoto, H;Ginzinger, DG;Jaffe, RB
背景：促肾上腺皮质激素是人胎儿肾上腺（HFA）的关键促肾上腺皮质激素。由于血管发育必须与器官生长协调，ACTH可能调节局部血管生成因子，从而影响HFA血管生成。我们之前已经证明ACTH上调HFA皮质细胞中的血管内皮生长因子。一个新的血管生成因子家族，血管生成素（Angs），也起着至关重要的作用。Ang1稳定血管，而Ang2破坏血管稳定，增加对血管生成刺激的反应。目的：探讨Angs及其受体Tie2在HFA中的表达及ACTH调控。设计、环境和患者：研究涉及hfa（14-24周）和成人肾上腺RNA的RNA、冷冻切片和原代细胞培养。主要观察指标：实时定量RT-PCR检测Angs和Tie2 mRNA水平，免疫染色定位Ang2和Tie2，实时定量RT-PCR、Western blot、ELISA检测ACTH对Angs的调节作用。结果：HFA Ang2 / Ang1 mRNA比值比成人高6.3倍（P < 0.001）。Ang2主要定位于HFA周围，而Tie2则定位于内皮细胞。在离体HFA皮质细胞中，ACTH以时间和剂量依赖的方式上调angmrna水平，且平衡倾向于Ang2。acth刺激的HFA皮质细胞和条件培养基中Ang2蛋白水平升高。8-溴腺苷cAMP和福斯克林模拟ACTH对Angs的作用。结论：与成人相比，高HFA Ang2 / Ang1比值可能反映了更大的血管重构。Angs，特别是Ang2，与血管内皮生长因子协同作用，可能介导促ACTH作用，确保HFA生长、类固醇生成和血管生成的协调。
Context: ACTH is the key tropic hormone for the human fetal adrenal (HFA). Because vascular development must be coordinated with organ growth, ACTH may regulate local angiogenic factors, thereby influencing HFA angiogenesis. We previously demonstrated that ACTH up-regulates vascular endothelial growth factor in HFA cortical cells. A newer angiogenic factor family, the angiopoietins (Angs), also plays critical roles. Ang1 stabilizes, whereas Ang2 destabilizes vessels, increasing responsiveness to angiogenic stimuli.Objective: The objective of this study was to investigate expression and ACTH regulation of Angs and their receptor Tie2 in the HFA.Design, Setting, and Patients: Studies were conducted involving RNA, frozen sections, and primary cell cultures from HFAs (14-24 wk) and human adult adrenal RNA.Main Outcome Measures: Angs and Tie2 mRNA levels were determined by real-time quantitative RT-PCR, Ang2 and Tie2 were localized by immunostaining, and ACTH regulation of Angs was investigated by real-time quantitative RT-PCR, Western blot, and ELISA.Results: Mean HFA Ang2 to Ang1 mRNA ratio was 6.3-fold higher than adult adrenals ( P < 0.001). Ang2 was localized predominantly in the HFA periphery, whereas Tie2 demonstrated endothelial localization. In isolated HFA cortical cells, ACTH up-regulated Ang mRNA levels in a time- and dose-dependent manner, with the balance favoring Ang2. Ang2 protein levels were elevated in ACTH-stimulated HFA cortical cells and conditioned medium. 8-Bromoadenosine cAMP and forskolin mimicked ACTH effects on the Angs.Conclusions: Higher HFA Ang2 to Ang1 ratios may reflect greater vascular remodeling than in the adult. Angs, particularly Ang2, in concert with vascular endothelial growth factor, may mediate ACTH tropic action, ensuring coordination of HFA growth, steroidogenesis, and angiogenesis.