PDF(Pubmed)
Abstract：
Estrogen is thought to have a role in slowing down aging and protecting cardiovascular and cognitive function. However, high doses of estrogen are still positively associated with autoimmune diseases and tumors with systemic inflammation. First, we administered exogenous estrogen to female mice for three consecutive months and found that the aorta of mice on estrogen develops inflammatory manifestations similar to Takayasu arteritis (TAK). Then, in vitro estrogen intervention was performed on mouse aortic vascular smooth muscle cells (MOVAS cells). Stimulated by high concentrations of estradiol, MOVAS cells showed decreased expression of contractile phenotypic markers and increased expression of macrophage-like phenotypic markers. This shift was blocked by tamoxifen and Krüppel-like factor 4 (KLF4) inhibitors and enhanced by Von Hippel-Lindau (VHL)/hypoxia-inducible factor-1α (HIF-1α) interaction inhibitors. It suggests that estrogen-targeted regulation of the VHL/HIF-1α/KLF4 axis induces phenotypic transformation of vascular smooth muscle cells (VSMC). In addition, estrogen-regulated phenotypic conversion of VSMC to macrophages is a key mechanism of estrogen-induced vascular inflammation, which justifies the risk of clinical use of estrogen replacement therapy.
摘要：
雌激素被认为具有减缓衰老和保护心血管和认知功能的作用。然而,高剂量的雌激素仍然与自身免疫性疾病和系统性炎症的肿瘤呈正相关。首先,我们连续3个月给予雌性小鼠外源性雌激素,发现雌激素作用下的小鼠主动脉出现类似于大动脉炎(TAK)的炎症表现.然后，对小鼠主动脉血管平滑肌细胞（MOVAS细胞）进行体外雌激素干预。在高浓度雌二醇的刺激下，MOVAS细胞显示收缩表型标志物的表达减少，巨噬细胞样表型标志物的表达增加。这种转变被他莫昔芬和Krüppel样因子4（KLF4）抑制剂阻断，并被VonHippel-Lindau（VHL）/缺氧诱导因子-1α（HIF-1α）相互作用抑制剂增强。这表明VHL/HIF-1α/KLF4轴的雌激素靶向调节诱导血管平滑肌细胞(VSMC)的表型转化。此外,雌激素调节的VSMC向巨噬细胞的表型转化是雌激素诱导的血管炎症的关键机制，这证明了临床使用雌激素替代疗法的风险。
