Dioxin Receptor Deficiency Impairs Angiogenesis by a Mechanism Involving VEGF-A Depletion in the Endothelium and Transforming Growth Factor-β Overexpression in the Stroma
Dioxin Receptor Deficiency Impairs Angiogenesis by a Mechanism Involving VEGF-A Depletion in the Endothelium and Transforming Growth Factor-β Overexpression in the Stroma
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DOI：
10.1074/jbc.m109.013292
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发表时间：
2009-09-11
影响因子：
4.8
通讯作者：
Fernandez-Salguero, Pedro M.
中科院分区：
文献类型：
--
作者：
Carlos Roman, Angel;Carvajal-Gonzalez, Jose M.;Fernandez-Salguero, Pedro M.
血管生成在人类疾病如癌症的发展和进展中具有关键作用。因此，鉴定新的血管生成的标志物和调节剂是一项关键的任务。二恶英受体（AhR）有助于血管内稳态和内皮细胞对毒素的反应，尽管所涉及的机制在很大程度上是未知的。在这里，我们表明，AhR基因敲除小鼠（AhR（-/-））在体内血管生成受损，损害肿瘤异种移植物的生长。主动脉环迁移实验和RNA干扰实验表明AhR（-/-）内皮细胞不能形成分支和管状结构。发现这种表型是血管内皮生长因子（VEGF）依赖性的，因为AhR（-/-）主动脉内皮细胞（MAEC）分泌较少量的活性VEGF-A，并且用VEGF-A治疗它们在培养物和体内挽救了血管生成。此外，向AhR（-/-）MAEC添加抗VEGF抗体减少血管生成。在低氧条件下用2-甲氧基紫杉醇治疗表明HIF-1 α以AhR依赖性方式调节内皮VEGF表达。重要的是，AhR-无效基质肌成纤维细胞产生增加的转化生长因子-β（TGF β）活性，其抑制人内皮细胞（HMEC）和AhR（-/-）小鼠中的血管生成，而HMEC与AhR（-/-）肌成纤维细胞或与其条件培养基的共培养抑制分支，其通过抗TGF β抗体恢复。此外，VEGF和TGF β活性在调节血管生成中协同作用，因为向AhR（-/-）MAEC中加入TGF β进一步降低了它们的低基础VEGF-A活性。因此，AhR通过需要内皮中的VEGF活化和基质中的TGF β失活的机制来调节血管生成。这些数据突出了AhR在心血管稳态中的作用，并表明该受体可以成为肿瘤发展过程中血管生成的新调节剂。
Angiogenesis has key roles in development and in the progression of human diseases such as cancer. Consequently, identifying the novel markers and regulators of angiogenesis is a critical task. The dioxin receptor (AhR) contributes to vascular homeostasis and to the endothelial response to toxins, although the mechanisms involved are largely uncharacterized. Here, we show that AhR-null mice (AhR(-/-)) have impaired angiogenesis in vivo that compromises tumor xenograft growth. Aortic rings emigration experiments and RNA interference indicated that AhR(-/-) endothelial cells failed to branch and to form tube-like structures. Such a phenotype was found to be vascular endothelial growth factor (VEGF)-dependent, as AhR(-/-) aortic endothelial cells (MAECs) secreted lower amounts of active VEGF-A and their treatment with VEGF-A rescued angiogenesis in culture and in vivo. Further, the addition of anti-VEGF antibody to AhR(-/-) MAECs reduced angiogenesis. Treatment under hypoxic conditions with 2-methoxyestradiol suggested that HIF-1 alpha modulates endothelial VEGF expression in an AhR-dependent manner. Importantly, AhR-null stromal myofibroblasts produced increased transforming growth factor-beta (TGF beta) activity, which inhibited angiogenesis in human endothelial cells (HMECs) and AhR(-/-) mice, whereas the co-culture of HMECs with AhR(-/-) myofibroblasts or with their conditioned medium inhibited branching, which was restored by an anti-TGF beta antibody. Moreover, VEGF and TGF beta activities cooperated in modulating angiogenesis, as the addition of TGF beta to AhR(-/-) MAECs further reduced their low basal VEGF-A activity. Thus, AhR modulates angiogenesis through a mechanism requiring VEGF activation in the endothelium and TGF beta inactivation in the stroma. These data highlight the role of AhR in cardiovascular homeostasis and suggest that this receptor can be a novel regulator of angiogenesis during tumor development.