Adenomyosis was associated not only with an increased incidence of preterm delivery, as previously reported, but also with an increased risk of second trimester miscarriage, preeclampsia, and placental malposition, which could lead to poor perinatal outcomes.

Apoptosis and inflammation generally exert opposite effects on tumorigenesis: apoptosis serves as a barrier to tumour initiation, whereas inflammation promotes tumorigenesis. Although both events are induced by various common stressors, relatively little is known about the stress-induced signalling pathways regulating these events in tumorigenesis. Here, we show that stress-activated MAP3Ks, ASK1 and ASK2, which are involved in cellular responses to various stressors such as reactive oxygen species, differentially regulate the initiation and promotion of tumorigenesis. ASK2 in cooperation with ASK1 functioned as a tumour suppressor by exerting proapoptotic activity in epithelial cells, which was consistent with the reduction in ASK2 expression in human cancer cells and tissues. In contrast, ASK1-dependent cytokine production in inflammatory cells promoted tumorigenesis. Our findings suggest that ASK1 and ASK2 are critically involved in tumorigenesis by differentially regulating apoptosis and inflammation.

Accumulation of hypoxia inducible factor-1α (HIF-1α) is commonly an acute and beneficial response to hypoxia, while chronically elevated HIF-1α is associated with multiple disease conditions including preeclampsia (PE), a serious hypertensive disease of pregnancy. However, the molecular basis underlying the persistent elevation of placental HIF-1α in PE and its role in the pathogenesis of PE are poorly understood. Here we report that Hif-1α mRNA and HIF-1± protein were elevated in the placentas of pregnant mice infused with angiotensin II type I receptor agonistic autoantibody (AT1-AA), a pathogenic factor in PE. Knockdown of placental Hif-1α mRNA by specific siRNA significantly attenuated hallmark features of PE induced by AT1-AA in pregnant mice including hypertension, proteinuria, kidney damage, impaired placental vasculature, and elevated maternal circulating soluble fms-like tyrosine kinase-1 (sFlt-1) levels. Next, we discovered that Hif-1α mRNA levels and HIF-1± protein levels were induced in an independent PE model with infusion of the inflammatory cytokine LIGHT (tumor necrosis factor superfamily member 14). SiRNA knockdown experiments also demonstrated that elevated HIF-1α contributed to LIGHT-induced PE features. Translational studies with human placentas showed that AT1-AA or LIGHT is capable of inducing HIF-1α in a hypoxia-independent manner. Moreover, increased HIF-1α was found to be responsible for AT1-AA or LIGHT-induced elevation of Flt-1 gene expression and production of sFlt-1 in human villous explants. Overall, we demonstrated that hypoxia-independent stimulation of HIF-1α gene expression in the placenta is a common pathogenic mechanism promoting disease progression. Our findings reveal new insight to PE and highlight novel therapeutic possibilities for the disease.

Background Preeclampsia (PE) is a prevalent hypertensive disorder of pregnancy and a leading cause of maternal and neonatal morbidity and mortality worldwide. This pathogenic condition is speculated to be due to placental abnormalities that contribute to the maternal syndrome. However, the specific factors and signaling pathways leading to impaired placentas and maternal disease development remain elusive. Methods and Results By using two independent animal models of PE—1) genetically-engineered pregnant mice with elevated adenosine exclusively in placentas, and 2) a pathogenic autoantibody-induced PE mouse model—we demonstrated here that chronically elevated placental adenosine was sufficient to induce hallmark features of PE including hypertension, proteinuria, small fetuses, and impaired placental vasculature. Genetic and pharmacologic approaches revealed that elevated placental adenosine coupled with excessive A2B adenosine receptor (ADORA2B) signaling contributed to the development of these features of PE. Mechanistically, we provided both human and mouse evidence that elevated placental CD73 is a key enzyme causing increased placental adenosine, thereby contributing to PE. Conclusions We determined that elevated placental adenosine signaling is a previously unrecognized pathogenic factor for PE. Moreover, our findings revealed the molecular basis underlying the elevation of placental adenosine and the detrimental role of excess placental adenosine in the pathophysiology of PE, and, thereby highlight novel therapeutic targets.