Preeclampsia is Associated with Altered Expression of Ferroptosis Biomarkers in Placental but not Maternal Vasculature.

Ferroptosis, an iron-dependent mechanism of programmed cell death, has been implicated in the pathogenesis of preeclampsia (PE). Here, we investigate the expression of key ferroptosis biomarkers in placental and decidua basalis tissues. Immunohistochemical (IHC) staining showed high expression of the ferroptosis suppressor, ferroptosis-suppressor protein 1 (FSP1), and the end product malondialdehyde (MDA), in healthy CD31-positive placental endothelium. The staining of all three markers was significantly reduced in PE placentas (P = 0.028). In vitro studies showed that an immortalized endometrial endothelial cell line, and its fetal counterpart, human umbilical vein endothelial cells, are intrinsically highly resistant to erastin-induced ferroptotic cell death compared with trophoblast, endometrial epithelial, and stromal fibroblast cell types. FSP1 was specifically expressed in the endometrial endothelial cells. Both FSP1 and another ferroptosis suppressor protein, GPX4, were degraded when the cells underwent ferroptotic cell death. Interestingly, staining of these same markers in maternal decidua basalis tissues did not show endothelium-specific staining, and no significant difference in staining was noted between healthy and PE tissues. Since previous studies have shown that endometrial cells can activate ferroptosis to produce pro-angiogenic cytokines, we posit that healthy placental endothelial cells activate ferroptosis, as evidenced by high MDA, to promote vasculature development without undergoing cell death, whereas PE placentas show reduced ferroptosis and vasculature underdevelopment. In contrast, both healthy and PE decidua basalis tissues were considered to be in a resting stage with regard to ferroptosis. Further studies are warranted to investigate how ferroptosis is regulated in both healthy and PE pregnancies.