Control of apoptosis during angiogenesis by survivin expression in endothelial cells
Control of apoptosis during angiogenesis by survivin expression in endothelial cells
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DOI：
10.1016/s0002-9440(10)64742-6
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发表时间：
2000-02-01
影响因子：
6
通讯作者：
Altieri, DC
中科院分区：
文献类型：
--
作者：
O'Connor, DS;Schechner, JS;Altieri, DC
研究血管生成过程中内皮细胞存活的控制机制。用有丝分裂原（包括血管内皮生长因子和碱性成纤维细胞生长因子）刺激静止的内皮细胞，可诱导细胞周期调节的凋亡抑制剂survivin上调约16倍。刺激丝裂原可迅速增加内皮细胞中survivin RNA的表达，在培养6 ~ 10小时后达到峰值，24小时后下降。炎症因子、肿瘤坏死因子α和白细胞介素-1不能诱导内皮细胞中survivin的表达。与二维培养相比，体外三维血管的形成与内皮细胞中survivin的强烈诱导有关。免疫组化结果显示，survivin在正常皮肤非增殖毛细血管内皮中表达量极低，而在肉芽组织新生血管中表达量大幅上调。在内皮细胞中重组表达绿色荧光蛋白survivin可降低caspase-3活性，抑制肿瘤坏死因子/环己亚胺诱导的细胞凋亡，这些发现表明survivin是内皮细胞在血管生成过程中表达的一种新的生长因子诱导的保护基因。治疗性操纵内皮中survivin的表达和功能可能影响代偿性或病理性（肿瘤）血管生成。
Mechanisms controlling endothelial cell survival during angiogenesis were investigated. Stimulation of quiescent endothelial cells with mitogens, including vascular endothelial growth factor and basic fibroblast growth factor, induced up to approximate to 16-fold up-regulation of the cell cycle-regulated apoptosis inhibitor survivin. Mitogen stimulation rapidly increased survivin RNA expression in endothelial cells, which peaked after 6 to 10 hours in culture and decreased by 24 hours. Inflammatory cytokines, tumor necrosis factor alpha, and interleukin-1 did not induce survivin expression in endothelial cells. Formation of three-dimensional vascular tubes in vitro was associated with strong induction of survivin in endothelial cells, as compared with two-dimensional cultures. By immunohistochemistry, survivin was minimally expressed in endothelium of nonproliferating capillaries of normal skin, whereas it became massively upregulated in newly formed blood vessels of granulation tissue in vivo. Recombinant expression of green fluorescent protein survivin in endothelial cells reduced caspase-3 activity and counteracted apoptosis induced by tumor necrosis factor alpha/cycloheximide, These findings identify survivin as a novel growth factor-inducible protective gene expressed by endothelial cells during angiogenesis. Therapeutic manipulation of survivin expression and function in endothelium may influence compensatory or pathological (tumor) angiogenesis.