ST2 gene products that are members of IL-1 receptor family are expressed in various cells such as growth-stimulated fibroblasts and Th2 helper T-cells, and recently, IL-33, which belongs to IL-1 family, was identified as the ligand for ST2L, the receptor type product of the ST2 gene. Subsequently, IL-33 and ST2L have been reported to be involved in Th2 immunity and inflammation, however, their functions on non-immunological cells are still obscure. Among non-immunological adhesive cells, vascular endothelial cells were reported to express both ST2 gene products and IL-33, therefore, we investigated the expression manner of the ST2 gene in vascular endothelial cells and the effect of IL-33 on endothelial cells. ST2 gene was expressed in each of the vascular endothelial cell types tested, and the expression was growth-dependent and down-regulated when the cells were differentiated to form vascular structures on the extracellular membrane matrix. IL-33 scarcely affected the growth and tube formation of the endothelial cells, but induced IL-6 and IL-8 secretion from endothelial cells with the rapid activation of extracellular signal-regulated kinase (ERK) 1/2, so IL-33 is supposed to involve in inflammatory reaction of vascular endothelial cells through its receptor, ST2L.

It is well known that withdrawal of progesterone from the maternal circulation is a critical stimulus to parturition in rodents, such as rats and mice. However, mechanisms that determine the timing of progesterone withdrawal are not completely understood. In the present study, we examined whether the vascular endothelial growth factor (VEGF) system in the corpus luteum (CL) contributes to the regulation of circulating progesterone levels and acts as a determinant of the timing of parturition in mice. We found that reduction in the expression levels of VEGF and VEGF receptor-2 in the CL precedes the impairment of luteal circulation and a series of events leading to parturition (i.e., reduction of plasma progesterone, enhancement of myometrium contractility, and onset of parturition). Blocking of VEGF signaling by using the inhibitor of VEGFR tyrosine kinase KRN633 at mid-pregnancy caused a similar sequence of events and induced preterm birth. These results suggest that the VEGF system in the CL plays a critical role in maintaining a high level of circulating progesterone, and determining the timing of parturition in mice.

Abstract. Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway during pregnancy contributes to several pathologic pregnancies, such as hypertension, preeclampsia, and intrauterine growth restriction, but its effects on the fetus have not been fully examined. To determine how inhibition of the VEGF signaling pathway affects the fetal vascular development of mid pregnancy, we treated pregnant mice daily with either the VEGF receptor-2 (VEGFR-2) tyrosine kinase inhibitor KRN633 (300 mg/kg, p.o.) or the vehicle from 13.5 to 15.5 day of pregnancy. On the 16.5 day of pregnancy, the vascular beds in the placenta and several organs of the fetus were visualized by fluorescent immunohistochemistry. All mice treated with KRN633 appeared healthy, and total numbers of fetuses per litter were unaffected. However, weights of the placenta and fetus from KRN633-treated mice were lower than those from the vehicle-treated ones. No external malformations and bleeding were observed in the placenta and fetus, whereas immunohistochemical analyses revealed that the vascular development in labyrinthine zone of placenta and fetal organs examined (skin, pancreas, kidney, and lung) were impaired by KRN633 treatment. These results suggest that inhibition of the VEGF signaling pathway during mid pregnancy suppresses vascular growth of both the placenta and fetus without obvious health impairments of mother mice and increases the risk of induction of intrauterine growth restriction.

Background Pregnancy and delivery are important life events for women. Recently, many connective tissue disease (CTD) patients have desired to become pregnant because of improved prognosis by early diagnosis and long-term remission under treatment with immunosuppressants. However, pregnancy in CTD patients is often associated with problems, including underlying disease exacerbation, complications of miscarriage and preterm birth, and light for dates (LFD) in the peripartum period. Whether these problems are associated with the activity of underlying disease or treatment with immunosuppressants is unclear. Objectives We analyzed the relationship between miscarriage, preterm birth, LFD, perinatal complications, and change in disease activity or dose of corticosteroid during pregnancy in our facility. Methods We retrospectively examined exacerbation of underlying disease, mode of delivery, rate of miscarriage and prematurity, neonatal birth weight, complications (e.g., threatened premature delivery and pregnancy-induced hypertension), and the dose of corticosteroid treatment during pregnancy for 8 years from October, 2006 to October, 2013. We also measured anti-SS-A antibody and antiphospholipid antibody. Results Sixty-three patients (77 pregnancies) who delivered at our institute were enrolled. At the time of pregnancy, the mean age was 31.9 years old and the mean disease duration was 7.1 years. Underlying diseases were as follows: systemic lupus erythematosus (32%), Sjögren syndrome (SS 28%), antiphospholipid syndrome (6%), and rheumatoid arthritis (16%). The activity of CTD was exacerbated in nine patients (11.3%) during pregnancy, and six required a high dose of corticosteroid therapy because of flare-up of CTD activity. Anti-SS-A antibody was positive in 35 cases (45.4%). However, there were no cardiac events and/or dermatological manifestations in newborns related to its antibody. Antiphospholipid antibody was positive in 19 cases (24.6%), and only one patient had a preterm birth considered as associated with its antibody. The rate of miscarriage was 7.7% and the rate of preterm birth was 17%. The rate of preterm birth was higher than normal (8%). The reason for preterm birth in all cases was termination of pregnancy dependent on flare-up of underlying CTD activity but on fetal problem. There was no relationship between the dose of corticosteroid and preterm complications, including preterm birth (13 cases), LFD (6 cases) or others (29 cases). We were able to safely increase the dose of corticosteroid for the treatment of underlying CTD during pregnancy in these patients. Conclusions In pregnancy complicated by CTD, preterm birth, LFD, and complications are strongly associated with the activity of underlying disease. Corticosteroids are not related to complications and can be safely used during pregnancy. Taken together, we need to strictly manage underlying disease with corticosteroids for pregnancy and delivery complicated by CTD. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014...

BackgroundRecently, many connective tissue disease (CTD) patients wish to become a mother because immunosuppressants and biologics enable to improve the outcome of underlying CTD and quality of life respectively. However, Pregnancies in CTD patients often have problems including underlying disease exacerbation, some complications during pregnancy especially in preterm birth, light for date (LFD) and premature rapture of membrane (PROM). Previous study identified that high clinical activities with hypocomplementemia and positive anti-dsDNA antibody were at highest risk for pregnancy loss and preterm delivery in SLE1). It is unclear whether these problems are associated with the activity of underlying CTD or immunosuppressant treatment.ObjectivesWe examine the issue of pregnancy and delivery complicated with CTD by the analysis of the cases in our institution.MethodsWe investigated the risk factors of preterm birth, LFD (light for dates) and perinatal complication from exacerbation of underlying disease, anti SS-A antibody, antiphospholipid antibody, doses of corticosteroid, immunosuppressants or biologics before pregnancy in 142 cases which were delivered in our institution.ResultsIn 23 among all cases underlying diseases were exacerbated, and these occurred more often in PM/DM (60%), MCTD (33.3%), RA (15.3%) and SLE (13.3%). In SLE, SS, MCTD and PM/DM, preterm births and LFD were closely related to disease exacerbation and dose of corticosteroid, pulse therapy, and these were extracted as risk factors for these perinatal complications. Preterm birth was also associated with low complement (CH50) and high titer of anti-dsDNA antibody, and LFD was associated with high titer of anti-dsDNA antibody before pregnancy. However, there was no significant association with these factors in threatened premature delivery and PROM. In RA, perinatal complications were not influenced by methotrexate and biologics before pregnancy. However, only LFD was related with doses of corticosteroid during pregnancy.ConclusionsWe extracted disease exacerbation and dose of corticosteroid, pulse therapy during pregnancy and also low complement, high titer of anti-double stranded DNA antibody before pregnancy as risk factors of pregnancy outcomes. In pregnancy complicated with CTD, we need to control the disease activity strictly, however, we should consider the increase or pulse therapy of corticosteroid carefully.References Clowse ME, Maqder LS, et al. The clinical utility of measuring complement and anti-dsDNA antibodies during pregnancy in patients with systemic lupus erythematosus. J Rheumatol. 2011 Jun; 38(6):1012–6. Disclosure of InterestNone declared