Department of Cardiology, Shenyang Northern Hospital, 83 Wenhua Road, Shenyang, Liaoning 110840 China.
Front Biosci (Landmark Ed). 2014 Jun 1;19(8):1215-26. doi: 10.2741/4277.
Knowledge about factors regulating vasculogenesis remains limited. The cellular repressor of E1A-stimulated gene (CREG) has been reported to be involved in maintaining cellular differentiation and endothelial homeostasis, thus we hypothesize that CREG may be a novel factor regulating vasculogenesis. By using mouse embryonic stem cells (ESC) derived embryoid body (EB) model, we confirmed expression of CREG was significantly up-regulated during EB differentiation. Overexpression of CREG in ESC led to accelerated cystic EB formation, increased endothelial differentiation and vasculogenesis, whereas knockdown of CREG produced opposite phenotypes. Moreover, we found expression of vascular endothelial growth factor (VEGF) was up-regulated and PI3K/Akt pathway was activated in CREG-overexpressing EB. Administration of VEGF neutralizing antibody or PI3K/Akt pharmacological inhibitor LY294002 blocked the vasculogenesis in CREG over-expressing EB, while supplement of VEGF rescued vasculogenesis deficiency in CREG knocked down EB. Further study by Western blot determined that PI3K/Akt was a downstream effector of VEGF. We identify CREG as a novel factor in regulating endothelial differentiation and vasculogenesis via VEGF/PI3K/Akt pathway.
关于调节血管发生的因素的知识仍然有限。细胞 E1A 刺激基因的抑制剂（CREG）已被报道参与维持细胞分化和内皮细胞稳态，因此我们假设 CREG 可能是调节血管发生的一个新的因素。通过使用小鼠胚胎干细胞（ESC）衍生的胚状体（EB）模型，我们证实 CREG 的表达在 EB 分化过程中显著上调。在 ESC 中过表达 CREG 导致囊泡状 EB 的形成加速、内皮分化和血管发生增加，而 CREG 的敲低则产生相反的表型。此外，我们发现 VEGF 的表达在过表达 CREG 的 EB 中上调，PI3K/Akt 通路被激活。给予 VEGF 中和抗体或 PI3K/Akt 药理学抑制剂 LY294002 阻断了 CREG 过表达 EB 中的血管发生，而 VEGF 的补充挽救了 CREG 敲低 EB 中的血管发生缺陷。进一步的 Western blot 研究确定 PI3K/Akt 是 VEGF 的下游效应物。我们确定 CREG 是通过 VEGF/PI3K/Akt 通路调节内皮细胞分化和血管发生的一个新的因素。
