RESUMO
Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies in Western societies. IUGR is a strong predictor of reduced short-term neonatal survival and impairs long-term health in children. Placental insufficiency is often associated with IUGR; however, the molecular mechanisms involved in the pathogenesis of placental insufficiency and IUGR are largely unknown. Here, we developed a mouse model of fetal-growth restriction and placental insufficiency that is induced by a midgestational stress challenge. Compared with control animals, pregnant dams subjected to gestational stress exhibited reduced progesterone levels and placental heme oxygenase 1 (Hmox1) expression and increased methylation at distinct regions of the placental Hmox1 promoter. These stress-triggered changes were accompanied by an altered CD8+ T cell response, as evidenced by a reduction of tolerogenic CD8+CD122+ T cells and an increase of cytotoxic CD8+ T cells. Using progesterone receptor- or Hmox1-deficient mice, we identified progesterone as an upstream modulator of placental Hmox1 expression. Supplementation of progesterone or depletion of CD8+ T cells revealed that progesterone suppresses CD8+ T cell cytotoxicity, whereas the generation of CD8+CD122+ T cells is supported by Hmox1 and ameliorates fetal-growth restriction in Hmox1 deficiency. These observations in mice could promote the identification of pregnancies at risk for IUGR and the generation of clinical interventional strategies.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Desenvolvimento Fetal/fisiologia , Retardo do Crescimento Fetal/prevenção & controle , Heme Oxigenase-1/fisiologia , Proteínas de Membrana/fisiologia , Placenta/imunologia , Insuficiência Placentária/imunologia , Complicações na Gravidez/imunologia , Progesterona/fisiologia , Estresse Psicológico/imunologia , Animais , Metilação de DNA , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Retardo do Crescimento Fetal/imunologia , Feto/imunologia , Feto/patologia , Heme Oxigenase-1/biossíntese , Heme Oxigenase-1/genética , Masculino , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Ruído/efeitos adversos , Placenta/metabolismo , Circulação Placentária , Insuficiência Placentária/etiologia , Gravidez , Complicações na Gravidez/genética , Complicações na Gravidez/psicologia , Progesterona/biossíntese , Progesterona/uso terapêutico , Regiões Promotoras Genéticas , RNA Mensageiro/genética , Estresse Psicológico/genéticaRESUMO
OBJECTIVE: To examine effects of fetoscopic laser occlusion of placental vascular anastomoses on umbilical venous volume flow in twin-to-twin transfusion syndrome. STUDY DESIGN: Absolute umbilical venous volume flow, measured preoperatively and 48 hours after fetoscopic laser occlusion was related to Doppler studies, bladder filling in donors, and anastomoses. RESULTS: Among 45 patients, recipients had decreased ductus venosus pulsatility index (ductus venosus-pulsatility index for veins, 1.16 vs 1.01; P < .001) and unchanged umbilical venous volume flow after fetoscopic laser occlusion (74.7 vs 74.5 mL; P = .407). Donors had decreased umbilical artery pulsatility (1.34 vs 1.11; P = .008), increased ductus venous-pulsatility index for veins (0.75 vs 0.91; P < .014), and significantly increased umbilical venous volume flow per kilogram by 52.3% (136.6 vs 208.0 mL/Kg/min; P < .001). Donor bladder filling occurred at higher umbilical venous volume flow per kilogram (142.7 vs 221.4 mL/Kg/min; P < .012). Increase in umbilical venous volume flow per kilogram correlated with the net difference in arteriovenous anastomoses (Pearson r = 0.403, P = .006). CONCLUSION: Fetoscopic laser occlusion in twin-to-twin transfusion syndrome corrects intertwin differences in umbilical venous volume flow by predominant effects in the donor. Reappearance of donor bladder filling correlates with correction of volume flow.