Porphyromonas gingivalis is a periodontal pathogen implicated in a range of pregnancy disorders that involve impaired spiral artery remodeling (ISAR) with or without fetal growth restriction (FGR). Using a rodent periodontitis model, we assessed the ability of P. gingivalis to produce ISAR and FGR in Sprague Dawley (SD) and Wistar (WIS) rats. Both infected SD and WIS rats developed ISAR, but only WIS rats developed FGR despite both rat strains having equivalent microbial loads within the placenta. Neither maternal systemic inflammation nor placental (fetal) inflammation was a feature of FGR in WIS rats. Unique to infected WIS rats, was loss of trophoblast cell density within the junctional zone of the placenta that was not present in SD tissues. In addition, infected WIS rats had a higher proportion of junctional zone trophoblast cells positive for cytoplasmic high temperature requirement A1 (Htra1), a marker of cellular oxidative stress. Our results show a novel phenomenon present in P. gingivalisinduced FGR, with relevance to human disease since dysregulation of placental Htra1 and placental oxidative stress are features of preeclamptic placentas and preeclampsia with FGR. Porphyromonas gingivalis, a Gram-negative bacterial pathogen, is one of the causative agents of generalized periodontitis in humans, which involves damage to the tooth-supporting structures 1. P. gingivalis is also implicated in a variety of pregnancy complications including recurrent spontaneous abortion 2 , preterm labor 3,4 , and preeclampsia with or without fetal growth restriction (FGR) 5-8. Similarly, experimental infection with P. gingivalis may lead to spontaneous preterm birth 9,10 , fetal death 11,12 , and/or fetal growth restriction 13-15 in rodents. Impaired spiral artery remodeling (ISAR) occurs when the normal physiologic process that converts high resistance uterine arteries into dilated, low resistance vessels is disrupted during pregnancy 16. ISAR has been detected in women suffering from recurrent spontaneous abortion, preterm labor, preeclampsia, and/or FGR 17-19 ; the same types of complications that have been linked to P. gingivalis infection 2-8. We previously provided proof of concept that P. gingivalis infection produces ISAR in Sprague Dawley (SD) rats 11. Surprisingly, FGR was not observed in our model. Since P. gingivalis-induced FGR is linked to overexpression of pro-inflammatory cytokines within the placenta 13-15 and has been seen in studies that used Wistar (WIS) rats 10,15 , we hypothesized that the host immune response to infection is a determinant in whether or not FGR occurs. FGR refers to the failure of the developing fetus to achieve optimal genetically determined growth in utero and is an important cause of fetal and neonatal morbidity and mortality 20,21. FGR is multifactorial and can be broadly categorized into maternal, fetal, and placental in origin. Some examples of maternal causes of FGR include underlying vascular disease, immune mediated diseases, substance abuse or toxicities, infectious diseases...

Impaired spiral artery remodeling (IRSA) underpins the great obstetrical syndromes. We previously demonstrated that intrauterine infection with the periodontal pathogen, Porphyromonas gingivalis, induces IRSA in rats. Since our previous studies only examined the end stage of arterial remodeling, the aim of this study was to identify the impact of P. gingivalis infection on the earlier stages of remodeling. Gestation day (GD) 11 specimens, a transition point between trophoblast-independent remodeling and the start of extravillous trophoblast invasion, were compared to late stage GD18 tissues. P. gingivalis was found in decidual stroma of GD11 specimens that already had reduced spiral artery remodeling defined as smaller arterial lumen size, increased retention of vascular smooth muscle, and decreased invasion by extravillous trophoblasts. At GD11, P. gingivalis-induced IRSA coincided with altered uterine natural killer (uNK) cell populations, decreased placental bed expression of interleukin-18 (IL-18) with increased production of temperature requirement A1 (Htra1), a marker of oxidative stress. By GD18, placental bed IL-18 and Htra1 levels, and uNK cell numbers were equivalent in control and infected groups. However, infected GD18 placental bed specimens had decreased TNF + T cells. These results suggest disturbances in placental bed decidual stroma and uNK cells are involved in P. gingivalis-mediated IRSA.

Impaired spiral artery remodeling (IRSA) underpins the great obstetrical syndromes. We previously demonstrated that intrauterine infection with the periodontal pathogen, Porphyromonas gingivalis, induces IRSA in rats. Since our previous studies only examined the end stage of arterial remodeling, the aim of this study was to identify the impact of P. gingivalis infection on the earlier stages of remodeling. Gestation day (GD) 11 specimens, a transition point between trophoblast-independent remodeling and the start of extravillous trophoblast invasion, were compared to late stage GD18 tissues. P. gingivalis was found in decidual stroma of GD11 specimens that already had reduced spiral artery remodeling defined as smaller arterial lumen size, increased retention of vascular smooth muscle, and decreased invasion by extravillous trophoblasts. At GD11, P. gingivalis-induced IRSA coincided with altered uterine natural killer (uNK) cell populations, decreased placental bed expression of interleukin-18 (IL-18) with increased production of temperature requirement A1 (Htra1), a marker of oxidative stress. By GD18, placental bed IL-18 and Htra1 levels, and uNK cell numbers were equivalent in control and infected groups. However, infected GD18 placental bed specimens had decreased TNF + T cells. These results suggest disturbances in placental bed decidual stroma and uNK cells are involved in P. gingivalis-mediated IRSA.