Low-dose Aspirin During Gestation Promotes Vascular Dysfunction and does not Ameliorate Maternal Hypertension in Rats Exposed to Innate Immune System Activation

Background: Daily low-dose aspirin after 12 weeks of gestation is recommended as a preventive intervention for women at high risk for preeclampsia, a hypertensive disorder of pregnancy with high rates of maternal and fetal mortality and morbidity. Activation of the innate immune system during pregnancy is implicated in the development of preeclampsia. Maternal exposure to synthetic CpG oligonucleotides (CpG ODN, specific ligand of the innate immune receptor Toll-like receptor 9) induces maternal hypertension, vascular dysfunction, and upregulation of cyclooxygenase enzymes in pregnant rats. Hypothesis: We hypothesized that maternal treatment with low-dose aspirin during gestation would ameliorate TLR9-induced hypertension and vascular dysfunction in pregnant rats. Methods: Pregnant Sprague-Dawley rats were treated with a synthetic CpG ODN (ODN2395) or vehicle on gestational day (GD) 14, 16, and 18. Aspirin treatment (or control) started on GD10 and continued throughout gestation for all groups [control (no treatment), ODN2395 (300 μg), aspirin (1.5 mg/kgBW), aspirin+ODN2395]. Blood pressure was measured on GD19 using the tail cuff method and mesenteric resistance artery (MES) function was assessed on GD21 using wire myography. Results: ODN2395-treated rats had higher blood pressure on GD19 compared to vehicle-treated dams and aspirin did not ameliorate ODN2395-induced hypertension (control: 97 ± 0.4 mmHg, ODN2395: 121 ± 7 mmHg, aspirin: 101 ± 5 mmHg, aspirin+ODN2395: 121 ± 7 mmHg, p Aspirin treatment increased MES sensitivity to PE (pEC50, ODN2395: 5.6 ± 0.1 vs. aspirin+ODN2395: 5.9 ± 0.1, ppEC50, ODN2395: 7.6 ± 0.1 vs. aspirin+ODN2395: 7.0 ± 0.1, pConclusion: Treatment with low-dose aspirin throughout gestation did not prevent the development of TLR9-induced maternal hypertension, augmented vascular sensitivity to α1-adrenergic receptor activation and attenuated endothelium-dependent dilation in rats exposed to innate immune system activation. The use of aspirin during gestation should be considered with caution in clinical cases associated with innate immune system-induced pregnancy complications.