Low-dose aspirin prevents LPS-induced preeclampsia-like phenotype via AQP-1 and the MAPK/ERK 1/2 pathway

Clinical studies suggest that early pregnancy is the critical window for the prevention of preeclampsia by low-dose aspirin (LDA). Abnormal extravillous trophoblast (EVT) cell invasion and spiral artery remodeling during early placentation have been observed in preeclampsia cases. Thus, we hypothesized LDA prevents preeclampsia by mitigating EVT migration/invasion and spiral artery remodeling dysfunction.A single systemic lipopolysaccharide (LPS) (1 μg/kg) injection was administrated in pregnant mice at e14.5 to induce a preeclampsia-like pregnant mouse model. We administered LDA (2.5 μg/g body weight/day) and observed the effects on LPS-induced preeclampsia-like symptoms by examining the placental histology, protein expression, EVT invasion, and spiral artery remodeling. In human EVT cell line, HTR-8/SVneo, we investigated cell invasion and migration by matrigel and wound healing assays, respectively. Signaling pathways were surveyed using inhibitors, siRNA transfections, and Western blot.LDA treatment significantly reversed the preeclampsia-like phenotype induced by LPS, as observed by decreases in hypertension, proteinuria, and fetal growth retardation. The numbers of pathological lesions, including excessive extracellular matrix deposition, endotheliosis, and collapsed glomerular capillaries in kidneys, were significantly lower in the LDA+LPS vs. the LPS group. LDA pretreatment eliminated placental lesions, including calcification, edema, and narrowed uterine spiral arteries and reduced aquaporin-1 (AQP-1) protein expression. In HTR-8/SVneo cells, LDA rescued the decreased cell migration and invasion induced by LPS. The phosphorylation of ERK1/2 was up-regulated and AQP-1 expression was decreased by LPS, which were reversed by LDA treatments. The effects of LDA were inhibited when AQP-1 expression was downregulated by siRNA transfection.This study provides new evidence that supports the use of LDA for the prevention of preeclampsia and suggests that the effects of LDA are mediated through a novel mechanism of a water channel, AQP-1, and MAPK/ERK 1/2 signaling.