ANP rescues the preeclamptic symptoms in Axl knockout mice by improving trophoblast function

Pre-eclampsia (PE) is characterized by maternal hypertension and/or proteinuria after 20 weeks of gestation. Shallow trophoblast invasion into spiral artery (SpA) and defective decidualization have been implicated in the pathogenesis of PE. However, the underlying mechanisms remain unclear. AXL receptor tyrosine kinase is a biomarker and therapeutic target for a variety of metastatic cancers while tumorigenesis and placentation share many features. In this study, a new function of AXL in promoting SpA remodeling and trophoblast invasion were demonstrated. The pregnant Axl knockout (Axl-/-) mice exhibited typical PE symptoms, including increased blood pressure and proteinuria. Artificially induced decidualization experiments showed that appeared normal, however, RNA-seq results of Axl-/- deciduoma revealed abnormal expression of a number of transcripts, including Corin, which encodes a cardiac protease that activates atrial natriuretic peptide (ANP). Treatment with ANP reversed the PE symptoms. Moreover, in decidua from women afflicted with PE, AXL level was significantly lower than that in normal pregnancies. These data show that the abnormality of decidua-derived AXL-CORIN-ANP affects maternal-fetal crosstalk and contributes to PE.