School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur 613401, India.
Department of Otorhinolaryngology, Head & Neck Surgery, University Hospital, LMU Munich, 81377 Munich, Germany.
Int J Mol Sci. 2019 Jul 5;20(13):3320. doi: 10.3390/ijms20133320.
The process of arteriogenesis is severely compromised in patients with diabetes mellitus (DM). Earlier studies have reported the importance of in promoting collateral outward remodeling. However, the role of in the presence of DM in outward vessel remodeling was not studied. We hypothesized that expression may be compromised in DM which may lead to impaired collateral vessel growth. Here, we investigated the relevance of the transcription factor for the process of collateral artery growth in diabetic mice. Induction of arteriogenesis by femoral artery ligation resulted in an increased expression of Egr-1 on mRNA and protein level but was severely compromised in streptozotocin-induced diabetic mice. Diabetes mellitus mice showed a significantly reduced expression of endothelial downstream genes Intercellular Adhesion Molecule-1 () and urokinase Plasminogen Activator (), relevant for extravasation of leukocytes which promote arteriogenesis. Fluorescent-activated cell sorting analyses confirmed reduced leukocyte recruitment. Diabetes mellitus mice showed a reduced expression of the proliferation marker Ki-67 in growing collaterals whose luminal diameters were also reduced. The Splicing Factor-1 (SF-1), which is critical for smooth muscle cell proliferation and phenotype switch, was found to be elevated in collaterals of DM mice. Treatment of DM mice with insulin normalized the expression of and its downstream targets and restored leukocyte recruitment. SF-1 expression and the diameter of growing collaterals were normalized by insulin treatment as well. In summary, our results showed that Egr-1 signaling was impaired in DM mice; however, it can be rescued by insulin treatment.
在患有糖尿病（DM）的患者中，动脉生成过程受到严重损害。早期研究已经报道了 在促进侧支向外重塑中的重要性。然而，在 DM 存在的情况下， 在外向血管重塑中的作用尚未得到研究。我们假设 表达可能在 DM 中受到损害，这可能导致侧支血管生长受损。在这里，我们研究了转录因子 对于糖尿病小鼠侧支动脉生长过程的相关性。股动脉结扎诱导的动脉生成导致 Egr-1 在 mRNA 和蛋白水平上的表达增加，但在链脲佐菌素诱导的糖尿病小鼠中严重受损。糖尿病小鼠显示出 内皮下游基因细胞间黏附分子-1 () 和尿激酶纤溶酶原激活物 () 的表达显著降低，这与促进动脉生成的白细胞渗出有关。荧光激活细胞分选分析证实白细胞募集减少。在生长侧支中，增殖标志物 Ki-67 的表达减少，其管腔直径也减小。剪接因子-1 (SF-1) 对于平滑肌细胞增殖和表型转换至关重要，在 DM 小鼠的侧支中发现其表达升高。用胰岛素治疗 DM 小鼠可使 及其下游靶基因的表达正常化，并恢复白细胞募集。SF-1 表达和生长侧支的直径也通过胰岛素治疗得到正常化。总之，我们的结果表明，Egr-1 信号在 DM 小鼠中受损，但可以通过胰岛素治疗来挽救。
