Aspirin Improves Uterine Artery Function in Hypercholesterolemic Preeclampsia

Abstract

Background: Excessive hypercholesterolemia in pregnancy increases the risk of preeclampsia (HC-PE), though the mechanisms remain unclear. We recently showed that uterine artery function is impaired in HC-PE pregnancies via activation of the TLR4 (toll-like receptor 4)/PGHS1 (prostaglandin H synthase 1) pathway. Low-dose aspirin lowers preeclampsia risk in high-risk pregnancies by inhibiting PGHS1, but its effects in HC-PE pregnancies are not known. Moreover, oxidized low-density lipoprotein (oxLDL) levels rise in HC-PE, potentially activating TLR4 and LOX-1 (lectin-like oxLDL receptor-1; scavenger receptor linked to vascular dysfunction in preeclampsia). However, whether this occurs in HC-PE is not known.

Methods: Sprague Dawley rats received a control or high-cholesterol diet (to induce HC-PE) from gestational day 6 to 20, with placebo or low-dose aspirin (1.5 mg/kg daily) given from gestational day 10 to 20. On gestational day 20, pregnancy outcomes and uterine artery function were assessed.

Results: Uterine artery blood flow velocity and placental weights were higher in HC-PE placebo-treated dams versus controls, but these were reduced by low-dose aspirin. Endothelium-dependent vasodilation was impaired in the uterine arteries of the HC-PE placebo group versus controls and was corrected by low-dose aspirin. Ex vivo inhibition of TLR4, PGHS1, or LOX-1 also normalized endothelium-dependent vasodilation in the HC-PE placebo-treated dams. Exposure to oxLDL in the bath (modeling a secondary hit) further impaired endothelium-dependent vasodilation in the uterine arteries of the HC-PE placebo group, partially via TLR4 and LOX-1, which was prevented by low-dose aspirin.

Conclusions: Low-dose aspirin improved uterine artery endothelial function in HC-PE pregnancies; likely by suppressing the TLR4/LOX-1/PGHS1 pathway.

Keywords: aspirin; cholesterol; preeclampsia; toll-like receptor 4; uterine artery.