Microcystin-LR inhibits early pregnancy by impairing the vascular network of luteum: Involvement of the MEK/ERK/SP1/VEGFR2 axis. (December 2022) - Guo, Meihong
Abstract: Microcystin-leucine-arginine (MC-LR) reduces the fertility of female mice, but the mechanism is unknown. We studied the effect of MC-LR on early pregnancy and elucidated its possible mechanism. The number of embryo beds and embryo volume decreased in pregnant mice at 6 or 8 days after fertilization after acute exposure to MC-LR. The corpus luteum secretes estrogen and progesterone, which are involved in embryo implantation and maintenance of early pregnancy. MC-LR exposure reduced luteal blood vessel branches and inhibited hormone synthesis. Functional blood vessels are essential to the maintenance of luteal structure and function. Reduced migration and tube-forming were also detected in human umbilical vascular endothelial cells (HUVECs) treated with MC-LR. MC-LR significantly decreased the expression of vascular endothelial growth factor receptor 2 (VEGFR2) in vivo and in vitro, which was responsible for the inhibited construction of the vascular network. The MEK/ERK/SP1 signal pathway mediated the decrease in VEGFR2 expression, and the agonists of phosphorylated extracellular regulated protein kinases (p-ERK) alleviated the anti-angiogenic effect of MC-LR. In conclusion, we demonstrated the toxicity of MC-LR on construction of vascular network in corpus luteum, which could provide a new perspective on female infertility or miscarriage caused by environmental factors. Graphical abstract: Image 1 Highlights: MC-LR induced embryo implantation disorder in pregnant mice. Corpus luteal vascular network was impacted by MC-LR. VEGFR2 expression was strongly down-regulated in ovarian of MC-LR treat mice and HUVECs. MEK/ERK/SP1 signal pathway mediated the decrease in VEGFR2 expression in HUVECs.