Placental sonic hedgehog pathway regulates foetal growth via insulin-like growth factor axis in preeclampsia.

BACKGROUND: Placental dysfunction is the underlying cause of common major disorders of pregnancy, such as foetal growth restriction (FGR) and preeclampsia. However, the mechanisms of placental dysfunction are not entirely elucidated. We previously reported 10 reliable preeclampsia pathways based on multiple microarray data sets, among which was the sonic hedgehog (SHH) pathway. Here we describe the significant role of SHH signalling involved in placental development and foetal growth. METHODS: The placental expression levels of surrogate markers of the SHH pathway, patched homolog 1 (PTCH1) and glioma-associated oncogene homolog 2 (GLI2), were evaluated using quantitative real-time polymerase chain reaction (qPCR), western blot analysis and immunohistochemistry. We investigated the underlying mechanisms of the SHH pathway in trophoblast syncytialization, a critical process for placental development and maturation, using primary cytotrophoblasts. Moreover, the potential roles of placental SHH signalling in the regulation of the insulin-like growth factor (IGF) axis were explored by pathway analysis of microarray data. Finally, the influence of SHH signalling on foetal growth was examined by placental administration of cyclopamine, an SHH pathway inhibitor, to pregnant mice. RESULTS: The SHH pathway was downregulated in preeclampsia placentas and its activation was highly correlated with birth weight. Trophoblast syncytialization was modulated by non-canonical SHH-adenylate cyclase (ADCY) signalling rather than canonical SHH-GLI signalling. The IGF1R pathway was regulated by both non-canonical SHH-ADCY signalling and canonical SHH-GLI signalling. Inhibition of placental SHH signalling significantly reduced foetal weight in mice. CONCLUSION: Placental development and foetal growth were regulated through the SHH pathway via the IGF axis.