Aspirin Improves Uterine Artery Function in Hypercholesterolemic Preeclampsia
Amanda A. de Oliveira, Floor Spaans, Murilo E. Graton, Angie Stokes, Raven Kirschenman, Anita Quon, Christy-Lynn M. Cooke, Sandra T. DavidgeBACKGROUND:
Excessive hypercholesterolemia in pregnancy increases the risk of preeclampsia, though the mechanisms remain unclear. We recently showed that uterine artery function is impaired in hypercholesterolemia-preeclampsia 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 hypercholesterolemia-preeclampsia pregnancies are not known. Moreover, oxidized low-density lipoprotein levels rise in hypercholesterolemia-preeclampsia, potentially activating TLR4 and LOX-1 (lectin-like oxLDL receptor-1; scavenger receptor linked to vascular dysfunction in preeclampsia). However, whether this occurs in hypercholesterolemia-preeclampsia is not known.
METHODS:
Sprague Dawley rats received a control or high-cholesterol diet (to induce hypercholesterolemia-preeclampsia) from gestational day 6 to 20, with placebo or low-dose aspirin (1.5 mg/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 hypercholesterolemia-preeclampsia placebo-treated dams versus controls, but these were reduced by low-dose aspirin. Endothelium-dependent vasodilation was impaired in the uterine arteries of the hypercholesterolemia-preeclampsia 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 hypercholesterolemia-preeclampsia placebo-treated dams. Exposure to oxidized low-density lipoprotein in the bath (modeling a secondary hit) further impaired endothelium-dependent vasodilation in the uterine arteries of the hypercholesterolemia-preeclampsia 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 hypercholesterolemia-preeclampsia pregnancies; likely by suppressing the TLR4/LOX-1/PGHS1 pathway.