Axl deficiency promotes preeclampsia and vascular malformations in mice

Preeclampsia (PE) is a significant complication of pregnancy, occurring in approximately 10% of pregnancies. However, the underlying mechanisms of this condition remain unclear. Placentation and tumorigenesis both share many characteristics, but PE is the result of insufficient placentation, in contrast to the overaggression of tumorigenesis. AXL is a biomarker and therapeutic target for multiple metastatic cancers. We hypothesized that its downregulation could play a crucial role in the development of PE. In our study, we demonstrated that pregnan<i>t Axl</i> ^<i>-/-</i> mice exhibited typical PE symptoms, such as hypertension, proteinuria, and inadequate trophoblast invasion and spiral artery remodeling. Cross-mating and embryo transplantation experiments confirmed that these phenotypes were caused by the decidua. RNA sequencing results revealed the abnormal expression of several transcripts in the decidua, including <i>Corin</i>, which encodes a cardiac protease responsible for activating atrial natriuretic peptide (ANP). ANP is a cardiac hormone that regulates sodium homeostasis and blood pressure. Chromatin immunoprecipitation-qPCR analysis indicated that the decreased CORIN in <i>Axl</i> ^<i>-/-</i> decidua was due to reduced signal transducer and activator of transcription 3 (STAT3) binding. Treatment with ANP successfully alleviated the PE symptoms. Furthermore, we observed that in PE decidua, the level of AXL was significantly lower compared to normal pregnancies. These findings suggest that the dysregulation of decidua-derived AXL-CORIN-ANP signaling disrupts maternal-fetal crosstalk and contributes to the development of PE.