Alterations in the placental endothelin system in response to hypoxia/ischemia and its effect on glycocalyx remodeling

Preeclampsia (PE) is one of the most common obstetrical complications, affecting 5-7% of pregnancies. PE is believed to derive in most cases from failure to adequately remodel the maternal arteries that feed the placenta, resulting in hypoxia/ischemia. In turn, the placenta secretes a number of factors that are believed to cause the maternal symptoms of hypertension, end-organ injury, and endothelial dysfunction. Among the most prevalent of these factors is the VEGF antagonist sFlt-1. We have recently shown that hypoxia-induced sFlt-1 release from placental cells is dependent on cleavage and solublization of the ECM protein Syndecan-1. Further, in preclinical models of placental ischemia-induced hypertension, antagonists of the endothelin-1 (Et-1) receptor attenuated maternal symptoms. Here, we hypothesize that Et-1 is dysregulated in response to placental ischemia, and that Et-1 antagonism could attenuate SDC-1 cleavage and sFlt-1 in response to hypoxia. We began by looking at changes in the Et-1 system in the placentas of the rodent Reduced Uterine Perfusion Pressure (RUPP) PE model. In response to ischemia, placental expression of EtA receptor was reduced by ~50% and EtB receptor was reduced by ~60%, while Et-1 expression was increased by ~50% by qRT-PCR. Interestingly, when we exposed BeWo placental trophoblasts to Et-1, there was a ~100% increase in the release of soluble SDC-1, an effect that was duplicated with EtA activation. Further, we found that Et-1 or EtA activation resulted in a 4-fold increase in secreted sFlt-1 from these cells as measured by ELISA. Together, these data suggest that the Et-1 system is dysregulated in the placenta in response to ischemia, and that ECM remodeling and sFlt-1 secretion are at least partially dependent on Et-1 signaling in PE. This work was partially supported by NIH grants P01HL51971, P20GM104357, and R01HL137791. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.