Alterations in the Placental Endothelin-1 System in Response to Hypoxia and Chronic Ischemia

Preeclampsia is one of the most common obstetrical complications, commonly characterized by new onset hypertension and proteinuria or other markers of end organ injury. In patients with preeclampsia, the arteries supplying the placenta develop abnormally, resulting in placental ischemia; widely believed to be responsible for the pathophysiology of this disorder. While the placenta is responsible for nutrient and waste exchange, it also releases numerous hormones from its interstitial and syncytialized trophoblasts important in pregnancy. Placental ischemia causes changes in placental hormone function, including endothelin-1 (ET-1). While ET-1 was initially characterized as a vasoconstrictor, it has been shown to be an important regulator of inflammatory and metabolic processes through its two receptors (ETA or ETB), though little is known about the role of the ET-1 system in the placenta. We hypothesized that chronic placental ischemia in vivo, and isolated hypoxia in vitro, would induce significant alteration in the expression of these individual components of the endothelin-1 system. Using the rodent reduced uterine perfusion pressure (RUPP) model to induce placental ischemia, we found that there was a significant (122±32 vs 45±12, p=0.05) decrease in the normalized expression of ETB, with a strong trend (112±26 vs 185±25, p=0.072) to increased ET-1 expression as measured by qRT-PCR. Interestingly, when we syncytialized BeWo choriocarcinoma cells and exposed them for 48 hours to oxygen tensions found in healthy (8%) and ischemic (1%) placentas, we found significant increases in ET-1 (205±79 vs 489±103, p=0.04), ETA (85±31 vs 276±67, p=0.04, and ETB (100±44 vs 388±68, p=0.05) gene expression. This suggests that individual cell types within the placenta are exhibiting differential response in endothelin signaling in response to hypoxia. The effect of endothelin on production of inflammatory cytokines was then determined. Compared to control (106±17) cells, both an ETB antagonist (163±12, p<0.05) and ET-1 itself (179±17, p<0.05) increased normalized TNF-α expression. Likewise, compared to controls (102±9), expression of the anti inflammatory IL-6 was significantly decreased with both ET-1 (69±11, p<0.05) and an ETA antagonist (70±9, p<0.05), suggesting that dysregulation of ET-1 signaling due to hypoxia could be an important regulator of inflammation in preeclampsia. Taken together, these data suggest that the placental ET-1 system could be a potential point of intervention for the management of preeclampsia. P01HL51971, P20GM104357, and R01HL137791 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.