HİF activation in the placenta by extracellular matrix composition

Objective: Preeclampsia (PE), a pregnancy disease that causes morbidity and mortality in women, is associated with impaired uterine extracellular matrix (ECM) remodeling and HIF function and inadequate trophoblast invasion. In mouse trophoblastic stem cells (TSCs), ECM can induce HIF via MAPK signaling pathway. In our study, we aimed to investigate the ECM-induced MAPK-HIF relationship in normal and preeclamptic human placentas. Method: In normal and PE term placentas, with double immunofluorescence staining of fibronectin, β3 integrin, phospho-MAPK3/1, HIF-1α, HIF-lβ, HIF-2α proteins, coexpressions were analyzed and cellular distributions were determined. Expressions of fibronectin, β3 integrin, HIF-1α, HIF-1β, HIF-2α and beta actin at protein and mRNA levels of placentas were evaluated by Western blot and qRT-PCR analysis respectively. The expressions of MAPK3/1 and phospho-MAPK3/1 proteins were examined by Western blot and MAPK1 and MAPK3 mRNAs were evaluated by qRT-PCR. Results: Expressions of fibronectin and β3 integrin at mRNA and protein levels in PE placentas did not change with respect to normal, whereas HIF (HIF-1α, HIF-1β and HIF-2α) expressions increased with respect to both mRNA and protein levels. MAPK1 expression in PE placentas was higher than normal at mRNA level but not changed at protein level. Expression of MAPK3 at mRNA and protein levels were the same between the groups. In normal and PE placentas, co-expression of fibronectin and HIF proteins, β3 integrin and HIF proteins and phospho-MAPK3/1 and HIF proteins were detected. Conclusion: In our study, for the first time, some evidence that ECM-induced MAPK-HIF pathway can be valid in normal and PE human placentas has been demonstrated. Extensive studies are needed to confirm the presence of ECM-induced MAPK-HIF pathway in human placenta and to understand the role of this pathway in the differentiation of placental cells. Key words: placenta, preeclampsia, extracellular matrix, MAPK, HIF