Aspirin Improves Uterine Artery Function in Hypercholesterolemic Preeclampsia.

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.