Combretastatin A-4 (CA4) is the lead compound of a relatively new class of vascular disrupting agents that target existing tumor blood vessels. Recent studies showed the CA4 might inhibit angiogenesis. However, the underlying molecular mechanisms by which CA4 exerts its anti-angiogenic effects are not fully understood. In this study, we revealed that CA4 inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration and capillary-like tube formation of human umbilical vascular endothelial cells (HUVECs). In in vivo assay, CA4 suppressed neovascularization in chicken chorioallantoic membrane (CAM) model and decreased the microvessel density in tumor tissues of a breast cancer MCF-7 xenograft mouse model. In addition, CA4 decreased the expression level and secretion of VEGF both in MCF-7 cells and HUVECs under hypoxia, as well as the activation of VEGFR-2 and its downstream signaling mediators following VEGF stimulation in HUVECs. Moreover, VEGF and VEGFR-2 expression in tumor tissues of the mouse xenograft model were down-regulated following CA4 treatment. Taken together, results from the current work provide clear evidence that CA4 functions in endothelial cell system to inhibit angiogenesis, at least in part, by attenuating VEGF/VEGFR-2 signaling pathway.

中文翻译：

---

Combretastatin A-4的抗血管生成作用和新的作用机理。

Combretastatin A-4（CA4）是针对现有肿瘤血管的一类相对较新的血管破坏剂的先导化合物。最近的研究表明，CA4可能抑制血管生成。但是，CA4发挥其抗血管生成作用的潜在分子机制尚未完全了解。在这项研究中，我们揭示了CA4抑制血管内皮生长因子（VEGF）诱导的人脐血管内皮细胞（HUVECs）增殖，迁移和毛细管样管形成。在体内测定中，CA4抑制了鸡绒膜尿囊膜（CAM）模型中的新血管形成，并降低了乳腺癌MCF-7异种移植小鼠模型肿瘤组织中的微血管密度。此外，缺氧条件下，CA4降低了MCF-7细胞和HUVEC中的表达水平和VEGF的分泌，以及HUVEC中VEGF刺激后VEGFR-2及其下游信号传导介质的激活。此外，在CA4处理后，小鼠异种移植模型的肿瘤组织中的VEGF和VEGFR-2表达下调。综上所述，当前工作的结果提供了明确的证据，证明CA4在内皮细胞系统中至少部分地通过减弱VEGF / VEGFR-2信号传导途径来抑制血管生成。