Front Biosci (Landmark Ed). 2014 Jun 1;19(7):1151-61. doi: 10.2741/4272.
Angiogenesis has long been considered as an important strategy for ischemic injury. It has been reported that cellular repressor of E1A-stimulated genes (CREG1) promotes human umbilical vein endothelial cell (HUVEC) proliferation, migration, and protects endothelial cell (EC) from apoptosis. However, its potential effect on angiogenesis remains undefined. In the present study, we investigated the role and mechanisms of CREG1 in promoting angiogenesis. We found that adenovirus-transduced CREG1 expression in HUVECs increases EC tube formation in matrigel and promotes neovascularization in matrigel plugs grafted into wild type mice. In addition, adenoviral CREG1 expression enhances filopodia formation, which is accompanied by increased expression of integrin-linked kinase (ILK) and activation of its downstream effector Cdc42. Hindlimb perfusion was significantly reduced after femoral artery ligation in CREG1 heterozygous knockout mice. Finally, adenoviral CREG1 was injected intramuscularly in gastrochemius and partially restores ischemic hindlimb perfusion. Our results demonstrated that CREG1 increases EC filopodia formation and vascular assembly via ILK-Cdc42 activation and promotes neovascularization, which might be a therapeutic target for ischemic injury.
血管生成一直被认为是缺血性损伤的重要策略。据报道，细胞 E1A 刺激基因的转录抑制剂（CREG1）可促进人脐静脉内皮细胞（HUVEC）的增殖、迁移，并保护内皮细胞（EC）免于凋亡。然而，其对血管生成的潜在影响尚不清楚。在本研究中，我们研究了 CREG1 在促进血管生成中的作用和机制。我们发现，腺病毒转导的 CREG1 在 HUVEC 中的表达增加了基质胶中 EC 管的形成，并促进了野生型小鼠基质胶塞中的新血管生成。此外，腺病毒 CREG1 的表达增强了丝状伪足的形成，这伴随着整合素连接激酶（ILK）的表达增加和其下游效应物 Cdc42 的激活。在 CREG1 杂合敲除小鼠的股动脉结扎后，后肢灌注明显减少。最后，腺病毒 CREG1 被肌肉内注射到比目鱼肌中，部分恢复了缺血后肢的灌注。我们的结果表明，CREG1 通过 ILK-Cdc42 的激活增加 EC 的丝状伪足形成和血管组装，并促进新血管生成，这可能是缺血性损伤的治疗靶点。
