Baicalein potently suppresses angiogenesis induced by vascular endothelial growth factor through the p53/Rb signaling pathway leading to G1/S cell cycle arrest
Baicalein potently suppresses angiogenesis induced by vascular endothelial growth factor through the p53/Rb signaling pathway leading to G1/S cell cycle arrest
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DOI：
10.1258/ebm.2011.010395
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发表时间：
2011-07-01
影响因子：
3.2
通讯作者：
Guo, Qinglong
中科院分区：
文献类型：
--
作者：
Ling, Yun;Chen, Yan;Guo, Qinglong
血管内皮生长因子（VEGF）是血管生成的关键调节因子。最近的研究表明，VEGF刺激内皮细胞生长，并通过重新激活GO细胞和减少G1期的持续时间来调节细胞周期。本研究检测了黄芩素（一种众所周知的黄酮类化合物）对VEGF诱导的血管生成的影响，并进一步研究了细胞周期调节剂对黄芩素抗血管生成作用的作用。经典的体内和体外模型，包括大鼠主动脉环模型，伤口愈合模型和管形成模型，用于评价体内和体外血管生成。黄芩素具有明显的血管生成抑制作用，显著抑制人脐静脉内皮细胞（HUVECs）的迁移，抑制管形成，减少VEGF诱导的新生血管生长。黄芩素减少VEGF受体2和细胞外信号调节蛋白激酶的磷酸化，这两个主要的信号元件调节内皮细胞增殖。黄芩素还抑制HUVEC的集落形成，进一步证实了增殖的抑制。细胞周期分析显示黄芩甙处理的HUVECs被阻滞于G1/S期。黄芩素还诱导G1期相关蛋白的表达下降，这些蛋白通常促进从G1期到S期的转变，包括细胞周期蛋白D、细胞周期蛋白E、cdk-4、cdk-6和p-Rb。与此相反，一些cdks和cyclins的上游蛋白，包括p16，p21，p27和p53，被黄芩素上调，表明黄芩素可能抑制血管生成，至少部分，通过对p53/Rb信号通路的影响。黄芩素可能通过抑制VEGF诱导的血管生成和内皮细胞增殖而发挥抗肿瘤作用。
Vascular endothelial growth factor (VEGF) is a key modulator of angiogenesis. Recent studies have shown that VEGF stimulates endothelial cell growth and modulates the cell cycle by reactivation of GO cells and by reducing the duration of the G1 phase. This study examined the effect of baicalein, a well-known flavonoid, on VEGF-induced angiogenesis and further investigated the role of cell cycle regulators on the antiangiogenic effects of baicalein. Classic in vivo and in vitro models, including a rat aortic ring model, a wound healing model and a tube formation model were used to evaluate angiogenesis in vivo and in vitro. Baicalein exerted marked inhibition of angiogenesis, significantly inhibited migration of human umbilical vein endothelial cells (HUVECs), suppressed tube formation and reduced new blood vessel growth inducted by VEGF. Baicalein reduced phosphorylation of VEGF receptor 2 and extracellular signal-regulated protein kinase, two major signaling elements modulating endothelial cell proliferation. Baicalein also inhibited colony formation by HUVECs, further confirming the suppression of proliferation. Cell cycle analysis demonstrated that baicalein-treated HUVECs were arrested in the G1/S phase. Baicalein also induced a decline in the expression of G1-related proteins that normally promote transition from the G1 phase to the S phase, including cyclin D, cyclin E, cdk-4, cdk-6 and p-Rb. In contrast, several proteins upstream of cdks and cyclins, including p16, p21, p27 and p53, were up-regulated by baicalein, indicating that baicalein may inhibit angiogenesis, at least in part, by effects on the p53/Rb signaling pathway. Baicalein could exert antitumor effects by inhibiting VEGF-induced angiogenesis and endothelial cell proliferation.