Reduced circulating miR-196b levels is associated with preeclampsia

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Positive correlations between circulating adiponectin and MMP2 in preeclampsia pregnant

Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)

Análise de inflamassoma induzido por urato monossódico em monócitos de gestantes portadoras de pré-eclampsia

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Pré-eclâmpsia e risco de alterações no ultrassom de crânio de recém-nascidos prematuros

Pós-graduação em Ginecologia, Obstetrícia e Mastologia - FMB

Influência do peso, volume e densidade absoluta da placenta no peso dos recém-nascidos de gestantes portadoras de hipertensão arterial ou Diabetes Mellitus

Influence of weight, volume and absolute placental density on the weight of newborns of pregnant women with arterial hypertension or Diabetes Mellitus

Placentation in the anteaters Myrmecophaga tridactyla and Tamandua tetradactyla (Eutheria, Xenarthra)

Background: Since Xenarthra are serious candidates for being basal to Eutheria, their characteristics, e.g. the placental system, influence perceptions of evolution. However, in the subgroup containing the anteaters, data are very limited. The present study aims to elucidate the nature of the feto-maternal interface in the anteater placenta and to interpret these data within an evolutionary context. Methods: Placentas of two species were investigated with histology, immunohistochemistry and transmission electron microscopy. Results: Remnants of the maternal vessel endothelium were absent, resulting in a fully haemochorial barrier throughout the placenta. Two structurally different parts, the villous and trabecular areas were complex and intermingled. In particular, the trabeculae which consisted of cellular, proliferative trophoblast, associated with connective tissue, were attached to the decidua. The villi contained fetal capillaries and hypertrophied mesenchymal cells that occured near the surface near the end of gestation. The surface of the villi consisted of flat, syncytial trophoblast, interspersed with proliferative trophoblast cells. Conclusions: Based on fundamental differences between anteaters and armadillos, we inferred that placental evolution was more complex than previously thought. The haemochorial pattern of anteaters was likely an ancient condition of xenarthrans. Consequently, villous placentation may be attributed, at least in part, by convergent evolution, but was also characterized by some features that were widespread among xenarthrans.

Toll-like receptor 9 activation: a novel mechanism linking placenta-derived mitochondrial DNA and vascular dysfunction in pre-eclampsia

Emerging evidence suggests that in addition to being the 'power houses' of our cells, mitochondria facilitate effector responses of the immune system. Cell death and injury result in the release of mtDNA (mitochondrial DNA) that acts via TLR9 (Toll-like receptor 9), a pattern recognition receptor of the immune system which detects bacterial and viral DNA but not vertebrate DNA. The ability of mtDNA to activate TLR9 in a similar fashion to bacterial DNA stems from evolutionarily conserved similarities between bacteria and mitochondria. mtDNA may be the trigger of systemic inflammation in pathologies associated with abnormal cell death. PE (pre-eclampsia) is a hypertensive disorder of pregnancy with devastating maternal and fetal consequences. The aetiology of PE is unknown and removal of the placenta is the only effective cure. Placentas from women with PE show exaggerated necrosis of trophoblast cells, and circulating levels of mtDNA are higher in pregnancies with PE. Accordingly, we propose the hypothesis that exaggerated necrosis of trophoblast cells results in the release of mtDNA, which stimulates TLR9 to mount an immune response and to produce systemic maternal inflammation and vascular dysfunction that lead to hypertension and IUGR (intra-uterine growth restriction). The proposed hypothesis implicates mtDNA in the development of PE via activation of the immune system and may have important preventative and therapeutic implications, because circulating mtDNA may be potential markers of early detection of PE, and anti-TLR9 treatments may be promising in the management of the disease.

The fetomaternal interface in the placenta of three species of armadillos (Eutheria, Xenarthra, Dasypodidae)

Background: Placental characters vary among Xenarthra, one of four supraordinal clades of Eutheria. Armadillos are known for villous, haemochorial placentas similar to humans. Only the nine-banded armadillo has been well studied so far. Methods: Placentas of three species of armadillos were investigated by means of histology, immunohistochemistry including proliferation marker, and transmission and scanning electron microscopy. Results: The gross anatomy differed: Euphractus sexcinctus and Chaetophractus villosus had extended, zonary placentas, whereas Chaetophractus vellerosus had a disk. All taxa had complex villous areas within the maternal blood sinuses of the endometrium. Immunohistochemistry indicated the validity of former interpretations that the endothelium of the sinuses was largely intact. Tips of the villi and the columns entering the maternal tissue possessed trophoblast cell clusters with proliferation activity. Elsewhere, the feto-maternal barrier was syncytial haemochorial with fetal vessels near the surface. Conclusions: Differences among armadillos occurred in regard to the extension of the placenta, whereas the fine structure was similar. Parallels to the human suggest that armadillos are likely to be useful animal models for human placentation.

Expression of angiogenic factors in placenta of stressed rats

The aim of the present study was to analyse the influence of stress on pregnant rats, particularly in terms of maternal, placental and fetal weight, placental morphology and placental gene expression of the angiogenic factors Vegfa and Pgf and their receptors. The parameters were evaluated on gestation Day 20. Maternal, fetal and placental weights were statistically lower in stressed animals than controls, suggesting abnormalities in gestational physiology. Morphologically the placentas of rats subjected to stress were reduced in size and weight, with few glycogen cells and a significant increase in the number of apoptotic cells. Stress caused an increase in placental gene expression of Vegfa (P < 0.05) and a reduction in Pgf, Flt1 and Kdr expression (P < 0.05). It has been suggested that increased VEGF is associated with vasodilatation and hypotension, but in this model persistent hypertension was present. This study suggests that the limited hypotensive Vegfa response to stress-induced hypertension could result from reduced expression of Flt1/Kdr disrupting specific VEGF pathways. These findings may elucidate one of the multiple possible factors underlying how stress modulates placental physiology, and could aid the understanding of stress-induced gestational disorders.

MyD88 signaling is directly involved in the development of murine placental Malaria

Malaria is a widespread infectious disease caused by the parasite Plasmodium. During pregnancy, malaria infection leads to a range of complications that can affect both the mother and fetus, including stillbirth, infant mortality, and low birth weight. In this study, we utilized a mouse model of placental malaria (PM) infection to determine the importance of the protein MyD88 in the host immune response to Plasmodium during pregnancy. Initially, we demonstrated that Plasmodium berghei NK65GFP adhered to placental tissue via chondroitin sulfate A and induced PM in mice with a C57BL/6 genetic background. To evaluate the involvement of MyD88 in the pathology of PM, we performed a histopathological analysis of placentas obtained from MyD88(-/-) and wild-type (WT) mice following infection on the 19th gestational day. Our data demonstrated that the detrimental placental alterations observed in the infected mice were correlated with the expression of MyD88. Moreover, in the absence of this protein, production of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) was significantly reduced in the infected mice. More importantly, in contrast to fetuses from infected WT mice, which exhibited a reduction in body weight, the fetuses from infected MyD88(-/-) mice did not display significant weight loss compared to their noninfected littermates. In addition, we observed a decrement of maternal care associated with malaria infection, which was attenuated in the MyD88-deficient mice. Collectively, the results of this study illustrate the pivotal importance of the MyD88 signaling pathway in the pathogenesis of placental malaria, thus presenting new possibilities for targeting MyD88 in therapeutic interventions.

Ruolo del Porcine Circovirus tipo 2 (PCV2) nella patologia riproduttiva del suino

La tesi è organizzata in 4 capitoli: -nel primo vengono brevemente riferite le patologie associate all’infezione da PCV2 con particolare riferimento all’iter diagnostico ed al ruolo rivestito dall’esame istologico e dalla identificazione dell’agente eziologico in situ contestualmente alle lesioni istologiche; -nel secondo viene presentato un iter diagnostico originale da applicare in condizioni di campo, qualora si voglia accertare la presenza del PCV2 nei tessuti dei prodotti di natimortalità/aborto del suino. In specifico si riferisce all’applicazione del protocollo in 2 aziende ed i risultati vengono analizzati per una revisione critica del protocollo impiegato; -nel terzo vengono presentati i risultati di un protocollo di infezione con PCV2 per via genitale tramite seme infetto. Scrofe convenzionali sono state sincronizzate per l’estro e fecondate con un’unica dose di seme PCV2 negativo alla PCR (gruppo controlli) o sperimentalmente esposto al PCV2 (gruppo infette). I risultati vengono analizzati in funzione delle ripercussioni che l’infezione precoce in gravidanza può produrre sulla scrofa (mancata gravidanza, ritorno in calore), sui feti e sugli invogli fetali. Viene stabilito il ruolo protettivo degli anticorpi circolanti al momento dell’infezione, stante l’evenienza che un basso titolo anticorpale si associa a viremia prolungata e maggiore numero di feti positivi al virus; -nel quarto viene presentato un esperimento sovrapponibile a quello riferito nel capitolo 3, però con la presenza anche di un gruppo di soggetti convenzionali vaccinati ed infettati con PCV2 durante la fecondazione artificiale usando seme sperimentalmente esposto al virus. Nella discussione dei risultati vengono enfatizzati 2 aspetti importanti nell’epidemiologia dell’infezione da PCV2: la eliminazione di virus è fortemente ridotta dalla vaccinazione, con conseguenze verosimilmente positive sulla circolazione del virus negli effettivi dell’allevamento; l’esposizione uterina è protetta dalla vaccinazione, stante la bassa percentuale di placente infette nel gruppo dei soggetti vaccinati rispetto a quelli non vaccinati e nei controlli.

Isufficienza Placentare nella Specie Equina

Lo sviluppo e la funzionalità della placenta influenzano direttamente la crescita ed il benessere del feto all'interno dell'utero, quindi qualsiasi problema strutturale o funzionale della placenta influenzerà lo sviluppo del feto. Lo scopo di questa tesi è stato quello di approfondire diversi aspetti clinici e clinico-patologici dell’insufficienza placentare nella specie equina, con l’intento di individuare dei parametri che possano essere di ausilio per l’identificazione precoce del puledro a rischio e della necessità di interventi terapeutici. La valutazione della concentrazione di lattato nel sangue e nel liquido amniotico potrebbe essere un utile strumento diagnostico per la diagnosi di acidosi metabolica associata ad ipossia/ischemia nel puledro e per identificare la necessità di un intervento precoce alla nascita. La risposta all’ipossia sembra essere mediata dall’HIF-1 e dall’HSF-1 anche nel puledro neonato, e se questi dati venissero confermati su un numero maggiore di animali, i due marcatori proteici e la MDA potrebbero essere utilizzati per la diagnosi di PAS nel puledro. L’esame di tutta l’unità placentare riveste un ruolo di fondamentale importanza per l’acquisizione di informazioni riguardo all’ambiente di vita intrauterino del puledro, ed è quindi auspicabile nella pratica ostetrica routinaria una maggiore attenzione all’esame della placenta, soprattutto in caso di patologie materno-fetali. Tra i parametri biochimici valutati al momento della nascita, la creatininemia e la glicemia possono fornire informazioni sull’efficienza dello scambio placentare ed essere quindi utilizzati per individuare puledri a rischio. Infine, lo sviluppo di una macro per il software ImageJ porta alla luce uno strumento nuovo, semplice da usare ed economico, per la valutazione morfometrica dell’arborizzazione dei villi placentari; tuttavia la ricerca necessità ulteriori indagini su un numero maggiore di animali per valutare le differenze morfometriche tra placente normali e patologiche.

Expression of adipokines and estrogen receptors in adipose tissue and placenta of patients with gestational diabetes mellitus

The purpose of this study was to assess the expression profile of genes with potential role in the development of insulin resistance (adipokines, cytokines/chemokines, estrogen receptors) in subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and placenta of pregnant women with gestational diabetes mellitus (GDM) and age-matched women with physiological pregnancy at the time of Caesarean section. qRT-PCR was used for expression analysis of the studied genes. Leptin gene expression in VAT of GDM group was significantly higher relative to control group. Gene expressions of interleukin-6 and interleukin-8 were significantly increased, whereas the expressions of genes for estrogen receptors alpha and beta were significantly reduced in SAT of GDM group relative to controls, respectively. We found no significant differences in the expression of any genes of interest (LEP, RETN, ADIPOR1, ADIPOR2, TNF-alpha, CD68, IL-6, IL-8, ER alpha, ER beta) in placentas of women with GDM relative to controls. We conclude that increased expression of leptin in visceral adipose depot together with increased expressions of proinflammatory cytokines and reduced expressions of estrogen receptors in subcutaneous fat may play a role in the etiopathogenesis of GDM.

Regulation of placental growth by aldosterone and cortisol

During pregnancy, trophoblasts grow to adapt the feto-maternal unit to fetal requirements. Aldosterone and cortisol levels increase, the latter being inactivated by a healthy placenta. By contrast, preeclamptic placental growth is reduced while aldosterone levels are low and placental cortisol tissue levels are high due to improper deactivation. Aldosterone acts as a growth factor in many tissues, whereas cortisol inhibits growth. We hypothesized that in preeclampsia low aldosterone and enhanced cortisol availability might mutually affect placental growth and function. Proliferation of cultured human trophoblasts was time- and dose-dependently increased with aldosterone (P < 0.04 to P < 0.0001) and inhibited by spironolactone and glucocorticoids (P < 0.01). Mineralo- and glucocorticoid receptor expression and activation upon agonist stimulation was verified by visualization of nuclear translocation of the receptors. Functional aldosterone deficiency simulated in pregnant mice by spironolactone treatment (15 μg/g body weight/day) led to a reduced fetal umbilical blood flow (P < 0.05). In rat (P < 0.05; R(2) = 0.2055) and human (X(2) = 3.85; P = 0.0249) pregnancy, placental size was positively related to plasma aldosterone. Autocrine production of these steroid hormones was excluded functionally and via the absence of specific enzymatic transcripts for CYP11B2 and CYP11B1. In conclusion, activation of mineralocorticoid receptors by maternal aldosterone appears to be required for trophoblast growth and a normal feto-placental function. Thus, low aldosterone levels and enhanced cortisol availability may be one explanation for the reduced placental size in preeclampsia and related disorders.

Neurogenic characteristics of placental stem cells in preeclampsia

Preeclampsia is associated with perinatal brain injury. Autologous placenta stem cell transplantation represents a promising future treatment option for neuroregeneration. The aim of this study was to compare the neuroregenerative capacity of preeclampsia-placenta stem cells to previously characterized placentas from uncomplicated pregnancies.