Acetylbritannilactone Modulates Vascular Endothelial Growth Factor Signaling and Regulates Angiogenesis in Endothelial Cells.
Acetylbritannilactone Modulates Vascular Endothelial Growth Factor Signaling and Regulates Angiogenesis in Endothelial Cells.
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乙酰布里坦内酯调节血管内皮生长因子信号传导并调节内皮细胞中的血管生成。
DOI：
10.1371/journal.pone.0148968
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Nie L
中科院分区：
文献类型：
--
作者：
Zhao J;Niu H;Li A;Nie L
研究了从旋覆花中提取的化合物1-O-乙酰旋覆花内酯（ABL）血管内皮生长因子（VEGF）信号传导和内皮细胞（EC）中的血管生成。我们发现，ABL促进VEGF诱导的细胞增殖，生长，迁移和管形成在培养的人内皮细胞。此外，ABL对VEGF诱导的Akt、MAPK p42/44和p38磷酸化以及上游VEGFR-2磷酸化的调节作用与体内VEGF依赖性Matrigel血管生成相关。此外，ABL（26 mg/kg/天）治疗的动物恢复血流明显早于对照动物，表明ABL影响体内缺血介导的血管生成和动脉生成。最后，我们证明ABL强烈降低细胞表面VEGFR-2的水平，增强VEGFR-2的内吞作用，这与抑制VE-cadherin一致，VE-cadherin是与VEGFR-2复合物形成相关的VEGF信号转导的负调节剂，但不改变VE-cadherin或VEGFR-2在EC中的表达。我们的研究结果表明，ABL可能作为一种新的治疗干预各种心血管疾病，包括慢性缺血，通过调节VEGF信号和调节血管生成。
The present study was conducted to determine the effects of 1-O-acetylbritannilactone (ABL), a compound extracted from Inula britannica L., on vascular endothelial growth factor (VEGF) signaling and angiogenesis in endothelial cells (ECs). We showed that ABL promotes VEGF-induced cell proliferation, growth, migration, and tube formation in cultured human ECs. Furthermore, the modulatory effect of ABL on VEGF-induced Akt, MAPK p42/44, and p38 phosphorylation, as well as on upstream VEGFR-2 phosphorylation, were associated with VEGF-dependent Matrigel angiogenesis in vivo. In addition, animals treated with ABL (26 mg/kg/day) recovered blood flow significantly earlier than control animals, suggesting that ABL affects ischemia-mediated angiogenesis and arteriogenesis in vivo. Finally, we demonstrated that ABL strongly reduced the levels of VEGFR-2 on the cell surface, enhanced VEGFR-2 endocytosis, which consistent with inhibited VE-cadherin, a negative regulator of VEGF signaling associated with VEGFR-2 complex formation, but did not alter VE-cadherin or VEGFR-2 expression in ECs. Our results suggest that ABL may serve as a novel therapeutic intervention for various cardiovascular diseases, including chronic ischemia, by regulating VEGF signaling and modulating angiogenesis.