Maternal hypertensive condition alters adipose tissue function and blood pressure sensitivity in offspring.

Preeclampsia (PE) is characterized by hypertension, proteinuria, and fetal growth restriction during pregnancy, suggesting that the preeclamptic intrauterine environment may affect the growth and health of the offspring. This study aimed to how maternal hypertension affects male offspring growth, focusing on lipid metabolism and blood pressure in mice. Female mice were infused with angiotensin II (Ang II) on gestational day 12. Dysregulation and accumulation of lipid were observed in the placenta of Ang II-induced maternal hypertensive dams, associating with fetal growth restriction. Ang II-offspring showed lower birth weight than in the control-offspring. Isolated and differentiated adipocyte from neonatal mice of Ang II-dams showed higher Pparγ mRNA expression compared with the control group. Lower body weight tendency had continued in Ang II-offspring during long period, body weight of Ang II-offspring caught up the control-offspring at 16 weeks of age. The adipose tissue of Ang II-offspring in adult also showed higher Pparγ mRNA expression with the accumulation of neutrophils and inflammatory monocytes than in those control. In addition, Ang II-offspring had higher basal blood pressure and higher sensitivity to hypertensive stimuli than in the control-offspring. Taken together, maternal hypertension induced by Ang II changes placental function, causing a lower birth weight. These changes in the intrauterine environment may affect adipocyte function and blood pressure of offspring after growth.

Gasdermin D regulates soluble fms-like tyrosine kinase 1 release in macrophages.

Preeclampsia (PE) is a serious complication, and soluble fms-like tyrosine kinase (sFLT1) released from the placenta is one of the causes of PE pathology. Trophoblasts are the primary source of sFLT1; however, monocytes/macrophages exist enough in the placenta can also secrete sFLT1. Sterile inflammatory responses, especially NLRP3 inflammasome and its downstream gasdermin D (GSDMD)-regulated pyroptosis, may be involved in the development of PE pathology. In this study, we investigated whether human monocyte/macrophage cell line THP-1 cells secrete sFLT1 depending on the NLRP3 inflammasome and GSDMD. To differentiate THP-1 monocytes into macrophages, treatment with phorbol 12-myristate 13-acetate (PMA) induced sFLT1 with interleukin (IL)- 1ß, but did not induce cell lytic death. IL-1ß secretion induced by PMA inhibited by deletion of NLRP3 and inhibitors of NLRP3 and caspase-1, but deletion of NLRP3 and these inhibitors did not affect sFLT1 secretion in THP-1 cells. Both gene deletion and inhibition of GSDMD dramatically decreased IL-1ß and sFLT1 secretion from THP-1 cells. Treatment with CA074-ME (a cathepsin B inhibitor) also reduced the secretion of both sFLT1 and IL-1ß in THP-1 cells. In conclusion, THP-1 macrophages release sFLT1 in a GSDMD-dependent manner, but not in the NLRP3 inflammasome-dependent manner, and this sFLT1 release may be associated with the non-lytic role of GSDMD. In addition, sFLT1 levels induced by PMA are associated with lysosomal cathepsin B in THP-1 macrophages. We suggest that sFLT1 synthesis regulated by GSDMD are involved in the pathology of PE.

Severe maternal stress alters placental function, resulting in adipose tissue and liver dysfunction in offspring of mice.

The developmental origins of health and disease (DOHaD) hypothesis is that future lifestyle diseases in offspring are associated with intrauterine origins in the mother; stress during pregnancy is a risk factor for these diseases in offspring. This study aimed to clarify association of maternal stress with placental dysfunction and offspring development in mice. We applied water stress for 24 h during late pregnancy to explore the metabolic response of offspring to a normal diet (ND) and high-fat diet (HFD). Placental functions were altered by maternal stress, reducing the birth weight of the offspring. In the later life of offspring fed with ND, maternal stress impaired systemic glucose tolerance and altered adipokine secretion in adipose tissue and/or liver. The female offspring of stress-induced dams were light in body weight with lower adipose tissue and smaller adipocytes in both the ND and HFD groups. Abnormal situations, such as dysregulation of plasma glucose levels and fatty liver despite and lower increases in body weight, were observed in the female offspring of stress-induced dams, especially in the HFD-treated group. These findings suggest that long-lasting abnormal conditions and responses to metabolic challenges in maternal stress-induced offspring are linked to placental dysregulation and fetal programming.

NLRP3 inflammasome is involved in testicular inflammation induced by lipopolysaccharide in mice.

PROBLEM: Systemic inflammation induced by infection, which is associated with testicular inflammation, predisposes males to subfertility. Recently, the nucleotide-binding oligomerization domain, leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) inflammasome was identified as a key mediator of inflammation, and excessive activation of the NLRP3 inflammasome was shown to contribute to the pathogenesis of a wide variety of diseases. However, the mechanisms underlying infectious inflammation in the testis remain unclear. We investigated the effect of lipopolysaccharide (LPS)-induced systemic inflammation on the role of the NLRP3 inflammasome in murine testes. METHOD OF STUDY: We performed in vivo and in vitro studies using an LPS-induced model of NLRP3 inflammasome activation and testicular inflammation. RESULTS: Intraperitoneal administration of LPS significantly impaired sperm motility in the epididymis of wild type (WT) and NLRP3-knockout (KO) mice. LPS administration stimulated interleukin (IL)-1ß production and secretion in the testes of WT mice, and these adverse effects were improved in the testes of NLRP3-KO mice. LPS administration also stimulated neutrophil infiltration as well as its chemoattractant C-C motif chemokine ligand 2 (CCL2) in WT testes, which were suppressed in NLRP3-KO testes. In in vitro cell culture, treatment with LPS and NLRP3 inflammasome activation significantly induced IL-1ß and CCL2 secretion from WT but not NLRP3-KO testicular cells. CONCLUSIONS: Taken together, our results suggest that testicular cells have the potential to secrete IL-1ß and CCL2 in an NLRP3 inflammasome-dependent manner and that these cytokines from the testis may further exacerbate testicular function, resulting in subfertility during infectious diseases.

Uncaria tomentosa extract (AC-11) improves pregnancy hypertension together with suppression of sFlt-1 and sEng.

Disruption of well-controlled reproductive functions leads to pregnancy complications such as hypertensive disorders of pregnancy (HDP). Uncaria tomentosa (Wild), known as cat's claw, is widely used for the treatment of a various types of health problems; AC-11 (AC-11®, hot-water extract of U. tomentosa) is unique phytochemical compound and has potential roles as anti-inflammatory or anti-oxidant processes. We investigated whether AC-11 has a protective effect on pathogenesis of HDP in vivo and production of anti-angiogenic factors (sFlt-1 and sEng, major factors for the onset of HDP) in in vitro. Non-pregnant or pregnant mice were administered AC-11 (4 mg/mL), then, angiotensin II (Ang II) was subcutaneously infused to increase blood pressure. Human placental tissues or human umbilical vein endothelial cells (HUVECs) were incubated with or without AC-11. Treatment with AC-11 significantly reduced blood pressure induced by Ang II infusion. The population of CD8+T cells, the ratio of CD8/CD4, and plasma interleukin-6 levels were increased by Ang II infusion, and were decreased by AC-11 both in pregnant and non-pregnant mice. In pregnant mice, plasma levels of sFlt-1 and sEng were decreased by AC-11. In in vitro cell culture of HUVECs or placental tissue culture, treatment with AC-11 significantly inhibited secretion of sFlt-1 and sEng. We suggest a novel role of AC-11 in regulating blood pressure by controlling the balance of T cell population and inflammatory cytokine production both in non-pregnant and pregnant conditions. In addition, AC-11 inhibits HDP-related factors, including sFlt-1 and sEng, suggesting that AC-11 may useful for relieving HDP.

Advanced maternal age induces fetal growth restriction through decreased placental inflammatory cytokine expression and immune cell accumulation in mice.

Advanced maternal age is a risk factor for female infertility, and placental dysfunction is considered one of the causes of pregnancy complications. We investigated the effects of advanced maternal aging on pregnancy outcomes and placental senescence. Female pregnant mice were separated into three groups: young (3 months old), middle (8-9 months old), and aged (11-13 months old). Although the body weights of young and middle dams gradually increased during pregnancy, the body weight of aged dams only increased slightly. The placental weight and resorption rate were significantly higher, and live fetal weights were reduced in a maternal age-dependent manner. Although mRNA expression of senescence regulatory factors (p16 and p21) increased in the spleen of aged dams, mRNA expression of p16 did not change and that of p21 was reduced in the placenta of aged dams. Using a cytokine array of proteins extracted from placental tissues, the expression of various types of senescence-associated secretory phenotype (SASP) factors was decreased in aged dams compared with young and middle dams. The aged maternal placenta showed reduced immune cell accumulation compared with the young placenta. Our present results suggest that models using pregnant mice older than 8 months are more suitable for verifying older human pregnancies. These findings suggest that general cellular senescence programs may not be included in the placenta and that placental functions, including SASP production and immune cell accumulation, gradually decrease in a maternal age-dependent manner, resulting in a higher rate of pregnancy complications.