Ruijing Zhang, Heng Wang, Xing Cheng, Keyi Fan, Tingting Gao, Xiaotong Qi, Siqi Gao, Guoping Zheng, Honglin Dong
Aging 2024 Jun 05Estrogen 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.
Ruijing Zhang, Heng Wang, Xing Cheng, Keyi Fan, Tingting Gao, Xiaotong Qi, Siqi Gao, Guoping Zheng, Honglin Dong. High estrogen induces trans-differentiation of vascular smooth muscle cells to a macrophage-like phenotype resulting in aortic inflammation via inhibiting VHL/HIF1a/KLF4 axis. Aging. 2024 Jun 05;16(11):9876-9898
PMID: 38843385
View Full Text