Low-dose aspirin reduces placental inflammation and restores angiogenic balance in a rat model of excessive hypercholesterolemia in pregnancy.

Low-dose aspirin is recommended to pregnant individuals at increased risk of preeclampsia to improve outcomes. We recently showed that low-dose aspirin improves uterine artery function in a rat model of excessive hypercholesterolemia (eHC) in pregnancy, a known risk factor for preeclampsia. However, its effects on placentas from male and female offspring remain unclear. Here, we examined how low-dose aspirin affects various placental inflammatory and angiogenic markers, as well as the maternal soluble fms-like tyrosine kinase receptor-1 (sFlt-1)/placental growth factor (PlGF) ratio, in eHC pregnancies. We hypothesized that low-dose aspirin reduces placental inflammation, leading to angiogenic balance in these pregnancies. Sprague-Dawley rats were fed a control diet or a high cholesterol diet (to model eHC) from gestational day (GD) 6 to 20, with placebo or low-dose aspirin administered from GD10 to 20. On GD20, placentas were collected and separated based on the fetal sex. eHC in pregnancy elevated maternal plasma sFlt-1 without altering PlGF, resulting in an increased sFlt-1/PlGF ratio; that did not occur with low-dose aspirin treatment. Moreover, placental sFlt-1 was increased in male, but not in female, fetuses, and was reduced by low-dose aspirin. Placental PlGF was reduced in males, but increased in females, of eHC pregnancies; low-dose aspirin restored placental PlGF in only the female placentas. NLRP3 (a major placental inflammatory pathway) levels were increased in only eHC male placentas and normalized by low-dose aspirin. These findings reveal that low-dose aspirin restores the maternal plasma sFlt-1/PlGF ratio and suppresses placental inflammation through sex-specific mechanisms in eHC pregnancies.NEW & NOTEWORTHY This study demonstrates that pregnancies complicated by excessive hypercholesterolemia have a higher maternal plasma sFlt-1/PlGF ratio driven by increased sFlt-1 levels, indicating an angiogenic imbalance. Importantly, this imbalance can be prevented with low-dose aspirin, an actionable therapeutic option during pregnancy. Low-dose aspirin suppressed placental inflammation (evidenced by decreased NLRP3 levels) and lowered placental-derived sFlt-1 via sex-specific mechanisms.