血管内皮细胞生长激活的XBP1在内皮细胞中的拼接对于血管生成至关重要
Lingfang Zeng1, Qingzhong Xiao, Mei Chen
1Cardiovascular Division, King's College London, 125 Coldharbour Lane, London, UK. lingfang.zeng@kcl.ac.uk or
Circulation
|March 27, 2013
概括
血管内皮细胞生长因子信号激活X盒结合蛋白1 (XBP1) 途径,这对于内皮细胞增殖和血管生成至关重要. 这一发现突出了调节血管形成的新机制.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 生理学 生理学 生理学
背景情况:
- 血管内皮细胞生长因子 (VEGF) 是血管生成的关键,通过控制内皮细胞的增殖.
- X-box结合蛋白1 (XBP1) 是已知的内细胞网膜压力的转子.
- 在此之前,VEGF信号与XBP1通路之间的相互作用是未知的.
研究的目的:
- 调查VEGF信号与XBP1通路之间的交叉声.
- 阐明XBP1在内皮细胞增殖和血管生成中的作用.
主要方法:
- 研究了VEGF对酶插入域受体 (KDR) 内化和与XBP1和需要酶1α (IRE1α) 的内醇相互作用的影响.
- 使用siRNA介导的KDR和XBP1.1的淘汰.
- 为XBP1 (XBP1ecko) 生成内皮细胞特异性淘汰赛小鼠,并进行基因转移 (Ad-XBP1s).
主要成果:
- VEGF诱导KDR内部化和与XBP1/IRE1α相互作用,导致IRE1α酸化和XBP1拼接.
- 拼接XBP1通过PI3K/Akt/GSK3β/β-catenin/E2F2信号调节内皮细胞的增殖和大小调节.
- 通过抑制Akt/GSK3β酸化,β-catenin核转移和E2F2表达,XBP1或IRE1α敲击降低了内皮细胞的增殖.
- XBP1ecko小鼠表现出视网膜血管生成和缺血诱导的血管生成受损;Ad-XBP1s基因转移或骨髓移植改善了血管生成.
结论:
- 在生长因子信号通路中,XBP1的功能是控制内皮细胞增殖.
- 在调节血管生成方面,XBP1起着至关重要的作用,特别是在对缺血的反应中.
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