title: Exposure to stimulatory CpG oligonucleotides during gestation induces maternal hypertension and excess vasoconstriction in pregnant rats.
abstract: Bacterial infections increase risk for pregnancy complications, such as preeclampsia and preterm birth. Unmethylated CpG DNA sequences are present in bacterial DNA and have immunostimulatory effects. Maternal exposure to CpG DNA induces fetal demise and craniofacial malformations; however, the effects of CpG DNA on maternal cardiovascular health have not been examined. We tested the hypothesis that exposure to synthetic CpG oligonucleotides (ODNs) during gestation would increase blood pressure and cause vascular dysfunction in pregnant rats. Pregnant and nonpregnant female rats were treated with CpG ODN (ODN 2395) or saline (Veh) starting on gestational day 14or corresponding day for the nonpregnant groups. Exposure to CpG ODN increased systolic blood pressure in pregnant (Veh: 121 ± 2 mmHg vs. ODN 2395: 134 ± 2 mmHg,P< 0.05) but not in nonpregnant rats (Veh: 111 ± 2 mmHg vs. ODN 2395: 108 ± 5 mmHg,P> 0.05). Mesenteric resistance arteries from pregnant CpG ODN-treated rats had increased contractile responses to U46619 [thromboxane A2(TxA2) mimetic] compared with arteries from vehicle-treated rats [Emax(%KCl), Veh: 87 ± 4 vs. ODN 2395: 104 ± 4,P< 0.05]. Nitric oxide synthase (NOS) inhibition increased contractile responses to U46619, and CpG ODN treatment abolished this effect in arteries from pregnant ODN 2395-treated rats. CpG ODN potentiated the involvement of cyclooxygenase (COX) to U46619-induced contractions. In conclusion, exposure to CpG ODN during gestation induces maternal hypertension, augments resistance artery contraction, increases the involvement of COX-dependent mechanisms and reduces the contribution of NOS-dependent mechanisms to TxA2-induced contractions in mesenteric resistance arteries.
authors.affiliation: Institute for Cardiovascular and Metabolic Diseases, Department of Obstetrics and Gynecology, University of North Texas Health Science Center, Fort Worth, Texas; styliani.goulopoulou@unthsc.edu.
authors.forename: Styliani
authors.initials: S
authors.lastname: Goulopoulou
authors.affiliation: Department of Physiology, Augusta University, Augusta, Georgia; and.
authors.forename: Camilla F
authors.initials: CF
authors.lastname: Wenceslau
authors.affiliation: Department of Physiology, Augusta University, Augusta, Georgia; and.
authors.forename: Cameron G
authors.initials: CG
authors.lastname: McCarthy
authors.affiliation: Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Department of Physiology, Augusta University, Augusta, Georgia; and.
authors.forename: R Clinton
authors.initials: RC
authors.lastname: Webb
mesh_terms: D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005865:Gestational Age; D046110:Hypertension, Pregnancy-Induced / Q000139:chemically induced* / Q000503:physiopathology; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000503:physiopathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000633:toxicity*; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000633:toxicity*
chemical_list: C527702:CpG ODN 2395; D016861:Cyclooxygenase Inhibitors; D009838:Oligodeoxyribonucleotides; D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases
keywords: Toll-like receptor 9; cyclooxygenase; hypertension; preeclampsia; vascular function