Treatment with the flavonoid, luteolin, attenuates the development of placental ischemia-induced hypertension in pregnant rats

Preeclampsia (PE) is a disease of hypertension and systemic vasoconstriction during pregnancy. Placental ischemia is implicated in PE by release of pro-hypertensive factors, like soluble Fms-like tyrosine kinase-1 (sFlt-1). Recently, we identified the bioflavonoid, luteolin, as a potent inhibitor of sFlt-1 and hypoxia-inducible factor 1α (HIF-1α, a major positive regulator of sFlt-1) in human placental cell lines and explants. However, the impact of luteolin in models of PE is unknown. We tested the hypothesis that luteolin attenuates placental ischemia-induced hypertension and lowers circulating sFlt-1 levels. Sprague-Dawley rats were started on luteolin treatment at gestational day 14 (20 mg/kg per day) or vehicle (0.5 g peanut butter) as well as placed in Reduced Uterine Perfusion Pressure (RUPP) placental ischemic or Sham surgery groups. The ensuing 4 experimental groups were: Sham+vehicle (N=14), Sham+luteolin (N=15), RUPP+vehicle (N=14), and RUPP+luteolin (N=15). On day 18, rats were implanted with carotid catheters for measurement of conscious mean arterial blood pressure (MAP) on gestational day 19. Luteolin treatment significantly attenuated RUPP-induced rises in maternal MAP (RUPP+vehicle: 118±2 vs. RUPP+luteolin: 108±1 mmHg, P<0.05) with no effect in Sham rats (Sham+vehicle: 105±1 mmHg; and Sham+luteolin: 104±2 mmHg, P>0.05). Circulating levels of sFlt-1 were elevated in RUPP+vehicle: 1.66±0.10 pg/mL vs. Sham+vehicle: 1.01±0.08 pg/mL (P<0.05) that were significantly reduced with luteolin treatment only in RUPP+luteolin: 1.09±0.11 pg/mL and not Sham+luteolin: 1.26±0.11 pg/mL (P<0.05). Total fetal weight was lower in RUPP+vehicle: 14±2 g vs. Sham+vehicle: 26±2 g (P<0.05) but was not impacted by luteolin treatment in either group (RUPP+luteolin: 12±1 g or Sham+luteolin: 26±2 g, P>0.05). Total placental weight was less in RUPP+vehicle: 3.3±0.6 g vs. Sham+vehicle: 6.4±0.4 g (P<0.05), which was not altered by luteolin treatment in either group (RUPP+luteolin: 3.1±0.4 g or Sham+luteolin: 6.1± 0.5 g, P>0.05). Overall, luteolin significantly attenuated placental ischemia-induced hypertension and reduced circulating sFlt-1 levels suggesting that naturally occurring flavonoids can be developed as therapeutics for PE. This work was supported by NIH 1R56HL157579-01. 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.