796: The role of single-stranded RNA in the development of preeclampsia

Preeclampsia (PE) affects approximately 10% of all pregnancies and is characterized by hypertension and proteinuria at or after 20 weeks gestation. We have shown previously that dsRNA plays a role in the development of PE. However, the role of ssRNA (derived from viruses and/or necrotic cells) and its receptors TLR7/8 in the development of PE is unknown. We propose that the ssRNA mimetics R837 and CLO97 trigger a maternal immune response that elicits PE-like symptoms in mice. Mice were divided into 6 groups: 1) C=non-pregnant control + vehicle, 2) CR=non-pregnant + R837 (TLR7 agonist), 3) CC=non-pregnant + CLO97 (TLR7/8 agonist), 4) P=pregnant control + vehicle, 5) PR= pregnant + R837, and 6) PC=pregnant + CLO97. Treatments were given by i.p. injection on days 13, 15, and 17 followed by euthanization on day 18. Blood pressure, aortic endothelial function, urinary protein concentration, and inflammation were measured. R837 and CLO97 induced inflammation exhibited by significantly increased spleen weight/body weight ratios and vascular and placental ICAM expression in all mice. However, CR and CC mice demonstrated no changes in blood pressure, endothelial function, or urinary protein excretion. In contrast, PR and PC mice had significantly increased systolic blood pressures and decreased endothelium-dependent aortic relaxation responses compared to P mice. Urinary protein excretion was increased significantly in PR mice, but there was no change in PC mice compared to P mice. PR and PC mice had no change in the total number of offspring or litter weight; however, fetal demise was significantly increased in both groups. These data indicate that ssRNA mimetics trigger an immune response that leads to hypertension and endothelial dysfunction during pregnancy only. Although excessive TLR7/8 activation increased fetal demise, only TLR7-specific activation caused proteinuria during pregnancy. These findings indicate the potential for TLR7/8 antagonists as treatments for hypertensive disorders of pregnancy.