Inhibition of angiogenesis by vitamin D-binding protein: characterization of anti-endothelial activity of DBP-maf.
Inhibition of angiogenesis by vitamin D-binding protein: characterization of anti-endothelial activity of DBP-maf.
复制标题
维生素 D 结合蛋白抑制血管生成：DBP-maf 抗内皮活性的表征。
DOI：
10.1007/s10456-005-9024-7
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发表时间：
2005
期刊：
影响因子：
9.8
通讯作者：
Swamy,Narasimha
中科院分区：
文献类型：
--
作者：
Kalkunte,Satyan;Brard,Laurent;Granai,CorneliusO;Swamy,Narasimha
血管生成是一个复杂的过程，涉及内皮细胞活化、增殖、迁移、管形成和毛细血管出芽的协调步骤，并有细胞内信号通路的参与。血管生成的调节为癌症治疗带来了巨大的潜力。我们的前期研究表明维生素D结合蛋白-巨噬细胞激活因子（DBP-maf）是一种有效的抗血管生成因子，在体内可抑制肿瘤生长。本研究旨在了解DBP-maf对人内皮细胞的作用及其抑制血管生成的机制。DBP-maf通过抑制DNA合成（μg/ml）抑制人内皮细胞（HEC）增殖。DBP-maf在72 h内可使HEC发生S期和G 0/G1期阻滞。DBP-maf以剂量依赖性方式有效地阻断VEGF诱导的HEC迁移、管形成。此外，DBP-maf抑制生长因子诱导的大鼠主动脉环试验中的微血管发芽。此外，DBP-maf通过降低VEGF介导的VEGFR-2和ERK 1/2（VEGF信号级联的下游靶点）的磷酸化来抑制VEGF信号传导。然而，Akt激活不受影响。这些研究共同表明，DBP-maf通过阻断关键步骤如HEC增殖、迁移、管形成和微血管发芽来抑制血管生成。DBP-maf通过抑制VEGR-2和ERK 1/2信号级联发挥其作用。了解DBP-maf抗血管内皮活性的细胞和分子机制，将使我们能够开发它作为一种新的肿瘤治疗药物的血管生成靶向。
Angiogenesis is a complex process involving coordinated steps of endothelial cell activation, proliferation, migration, tube formation and capillary sprouting with participation of intracellular signaling pathways. Regulation of angiogenesis carries tremendous potential for cancer therapy. Our earlier studies showed that vitamin D-binding protein-macrophage activating factor (DBP-maf) acts as a potent anti-angiogenic factor and inhibits tumor growthin vivo. The goal of this investigation was to understand the effect of DBP-maf on human endothelial cell (HEC) and the mechanism of angiogenesis inhibition. DBP-maf inhibited human endothelial cell (HEC) proliferation by inhibiting DNA synthesis (μg/ml). DBP-maf significantly induced S- and G0/G1-phase arrest in HEC in 72 h. DBP-maf potently blocked VEGF-induced migration, tube-formation of HEC in a dose dependent manner. In addition, DBP-maf inhibited growth factor-induced microvessel sprouting in rat aortic ring assay. Moreover, DBP-maf inhibited VEGF signaling by decreasing VEGF-mediated phosphorylation of VEGFR-2 and ERK1/2, a downstream target of VEGF signaling cascade. However, Akt activation was not affected. These studies collectively demonstrate that DBP-maf inhibits angiogenesis by blocking critical steps such as HEC proliferation, migration, tube formation and microvessel sprouting. DBP-maf exerts its effect by inhibiting VEGR-2 and ERK1/2 signaling cascades. Understanding the cellular and molecular mechanisms of anti-endothelial activity of DBP-maf will allow us to develop it as an angiogenesis targeting novel drug for tumor therapy.