Hypoxia influences the vascular expansion and differentiation of embryonic stem cell cultures through the temporal expression of vascular endothelial growth factor receptors in an ARNT-dependent manner.
Hypoxia influences the vascular expansion and differentiation of embryonic stem cell cultures through the temporal expression of vascular endothelial growth factor receptors in an ARNT-dependent manner.
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DOI：
10.1002/stem.316
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发表时间：
2010-04
期刊：
影响因子：
5.2
通讯作者：
Ramirez-Bergeron, Diana L.
中科院分区：
文献类型：
--
作者：
Han, Yu;Kuang, Shu-Zhen;Gomer, Alla;Ramirez-Bergeron, Diana L.
关键词：
对低氧（O2）张力（缺氧）的适应性反应是由异二聚体转录因子缺氧诱导因子（HIF）介导的。当被缺氧稳定时，bHLH-PAS α-和β-（HIF-1β或ARNT）HIF复合物调节包括血管内皮生长因子（VEGF）在内的多个基因的表达。为了解决缺氧促进血管发育的机制，我们利用胚胎干细胞（ESC）分化培养物，其发育成模拟早期胚胎发育的胚状体（EB）。值得注意的是，低O2水平促进野生型（WT）ESC培养物中的血管发育和成熟，通过增加CD 31+内皮细胞（EC）和出芽血管生成EB的数量来测量，但在Arnt−/−和Vegf−/− ESC培养物中无效。因此，我们认为缺氧促进了内皮细胞的产生，并有助于血管的发育和成熟。我们的研究结果进一步表明，缺氧改变VEGF受体Flk-1（VEGFR-2）和拮抗受体Flt-1（VEGFR-1）的膜和可溶性形式的时间表达。此外，这些受体在分化的Arnt−/−和Vegf−/− EB中明显表达。这些结果支持现有的模型，其中VEGF信号在特定的生物学事件中受到严格调控，但也提供了重要的新证据，即在响应生理缺氧时，HIF介导了整个EB分化过程中VEGF受体的独特化学计量模式，类似于胚胎发生过程中血管网络的形成。
Adaptive responses to low oxygen (O2) tension (hypoxia) are mediated by the heterodimeric transcription factor Hypoxia Inducible Factor (HIF). When stabilized by hypoxia, bHLH-PAS α- and β-(HIF-1β or ARNT) HIF complex regulate the expression of multiple genes including vascular endothelial growth factor (VEGF). In order to address the mechanism(s) through which hypoxia contributes to blood vessel development, we utilized embryonic stem cell (ESC) differentiation cultures that develop into embryoid bodies (EBs) mimicking early embryonic development. Significantly, low O2 levels promote vascular development and maturation in wild type (WT) ESC cultures measured by an increase in numbers of CD31+ endothelial cells (ECs) and sprouting angiogenic EBs but refractory in Arnt−/− and Vegf−/− ESC cultures. Thus, we propose that hypoxia promotes the production of ECs and contributes to the development and maturation of vessels. Our findings further demonstrate that hypoxia alters the temporal expression of VEGF receptors Flk-1 (VEGFR-2) and the membrane and soluble forms of the antagonistic receptor Flt-1 (VEGFR-1). Moreover, these receptors are distinctly expressed in differentiating Arnt−/− and Vegf−/− EBs. These results support existing models wherein VEGF signaling is tightly regulated during specific biological events, but also provide important novel evidence that, in response to physiological hypoxia, HIF mediates a distinct stoichiometric pattern of VEGF receptors throughout EB differentiation analogous to the formation of vascular networks during embryogenesis.
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DOI：
10.1083/jcb.200709114
发表时间：
2008-06-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kappas NC;Zeng G;Chappell JC;Kearney JB;Hazarika S;Kallianos KG;Patterson C;Annex BH;Bautch VL
通讯作者：
Bautch VL
影响因子：
3.5
作者：
Hermant B;Desroches-Castan A;Dubessay ML;Prandini MH;Huber P;Vittet D
通讯作者：
Vittet D
影响因子：
20.3
作者：
Bautch, VL;Redick, SD;Rapoport, R
通讯作者：
Rapoport, R
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
10.4
作者：
Li, X.;Claesson-Welsh, L.
通讯作者：
Claesson-Welsh, L.