Calcifediol Suppressed Placental Inflammation and Improved Pregnancy Outcomes by Targeting JAK/STAT Signaling Pathway in Preeclampsia

Abstract

ABSTRACT Background Preeclampsia (PE) is a pregnancy‐specific syndrome, which has been recognized as a leading cause of maternal and neonatal morbidity and mortality worldwide. Calcifediol (25‐hydroxy Vitamin D3) was reported to be closely associated with pregnancy outcomes such as preeclampsia, gestational hypertension, and gestational diabetes. Nevertheless, the specific role of calcifediol remains obscure in PE. Methods The pregnant rats were treated with L‐NAME (50 mg/kg/day) to establish PE models. Histopathological injury of placental tissues was observed by HE staining. Systolic blood pressure, proteinuria, and urine volume were measured to evaluate the symptoms of PE. The neonatal birth rate, pup's body length and weight were determined to assess pregnancy outcomes. The placental cytokines and serum sFlt‐1/PIGF ratio were detected by ELISA analysis. The protein levels were measured by Western blotting analysis. Results Calcifediol treatment alleviated the histopathological injury placental tissues of PE rats. In addition, calcifediol improves PE symptoms by attenuating hypertension, proteinuria and urine volume. Besides, calcifediol ameliorated pregnancy outcomes by enhancing live birth rate, neonatal birth length, and neonatal birth weight. Moreover, calcifediol restrained pro‐inflammatory cytokines in placental tissues and facilitated serum sFlt‐1/PIGF balance in PE rats. Mechanistically, calcifediol is closely associated with the inactivation of JAK/STAT signaling, as evidenced by the reduction of the phosphorylated JAK1, STAT1, and STAT3 proteins in placental tissues. Conclusions Calcifediol elicits significant therapeutic effects in L‐NAME‐induced PE rat models by ameliorating PE symptoms and pregnancy outcomes, attenuating inflammatory responses and alleviating histopathological damage.