Department of Pathology, Yale University School of Medicine, New Haven, Conn 06520, USA.
Arterioscler Thromb Vasc Biol. 2010 Dec;30(12):2553-61. doi: 10.1161/ATVBAHA.110.214999. Epub 2010 Sep 23.
The goal of this study was to investigate the novel hypothesis that bone marrow kinase in the X chromosome (Bmx), an established inflammatory mediator of pathological angiogenesis, promotes lymphangiogenesis.
We have recently demonstrated a critical role for Bmx in inflammatory angiogenesis. However, the role of Bmx in lymphangiogenesis has not been investigated. Here, we show that in wild-type mice, Bmx is upregulated in lymphatic vessels in response to vascular endothelial growth factor (VEGF). In comparison with wild-type mice, Bmx-deficient mice mount weaker lymphangiogenic responses to VEGF-A and VEGF-C in 2 mouse models. In vitro, Bmx is expressed in cultured human dermal microvascular lymphatic endothelial cells. Furthermore, pharmacological inhibition and short interfering RNA mediated silencing of Bmx reduces VEGF-A and VEGF-C-induced signaling and lymphatic endothelial cell tube formation. Mechanistically, we demonstrated that Bmx differentially regulates VEGFR-2 and VEGFR-3 receptor signaling pathways: Bmx associates with and directly regulates VEGFR-2 activation, whereas Bmx associates with VEGFR-3 and regulates downstream signaling without an effect on the receptor autophosphorylation.
Our in vivo and in vitro results provide the first insight into the mechanism by which Bmx mediates VEGF-dependent lymphangiogenic signaling.
本研究旨在探讨一个新假说，即 X 染色体骨髓激酶（Bmx）作为病理性血管生成的炎症介质，可促进淋巴管生成。
我们最近证实了 Bmx 在炎症性血管生成中的关键作用。然而，Bmx 在淋巴管生成中的作用尚未得到研究。在这里，我们表明在野生型小鼠中，Bmx 在内皮生长因子（VEGF）的刺激下在上皮细胞中上调。与野生型小鼠相比，Bmx 缺陷型小鼠在 2 种小鼠模型中对 VEGF-A 和 VEGF-C 的淋巴管生成反应较弱。在体外，Bmx 在培养的人真皮微血管淋巴管内皮细胞中表达。此外，Bmx 的药理学抑制和短发夹 RNA 介导的沉默可减少 VEGF-A 和 VEGF-C 诱导的信号转导和淋巴管内皮细胞管状形成。从机制上讲，我们证明了 Bmx 可差异调节 VEGFR-2 和 VEGFR-3 受体信号通路：Bmx 与 VEGFR-2 结合并直接调节其激活，而 Bmx 与 VEGFR-3 结合并调节下游信号转导，而对受体自身磷酸化无影响。
我们的体内和体外结果首次提供了有关 Bmx 介导 VEGF 依赖性淋巴管生成信号转导的机制的见解。
