Placental Sonic Hedgehog Pathway Regulates Fetal Growth via the IGF Axis in Preeclampsia

Context: Placental dysfunction is the underlying cause of common major disorders of pregnancy, such as fetal growth restriction 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. In this study, we describe the significant role of SHH signaling involved in placental development and fetal growth. Design: The placental expression levels of surrogate markers of the SHH pathway, patched homolog 1 (PTCH1) and glioma-associated oncogene homolog (GLI) 2, were evaluated using quantitative real-time PCR, 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 signaling in the regulation of the IGF axis were explored by pathway analysis of microarray data. Finally, the influence of SHH signaling on fetal 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 noncanonical SHH-adenylate cyclase (ADCY) signaling rather than canonical SHH-GLI signaling. The IGF1 receptor pathway was regulated by both noncanonical SHH-ADCY signaling and canonical SHH-GLI signaling. Inhibition of placental SHH signaling significantly reduced fetal weight in mice. Conclusion: Placental development and fetal growth were regulated through the SHH pathway via the IGF axis.