Progesterone induced blocking factor improves blood pressure, mitochondrial dysfunction and reactive oxygen species in response to sFlt‐1 induced hypertension during pregnancy

Abstract

Preeclampsia (PE) is characterized by new onset hypertension in association with placental ischemia, reduced fetal weight, elevated soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and placental mitochondrial (mt) dysfunction and oxidative stress (ROS). Infusion of sFlt‐1 causes hypertension and endothelial and renal dysfunction in pregnant rodent models of PE. However a role for sFlt‐1 in causing mt dysfunction and ROS is unknown. Progesterone induced blocking factor (PIBF), is a product of progesterone signaling in early pregnant which controls pro‐inflammatory processes and thus markers of endothelial dysfunction. We have previously shown that progesterone supplementation improves markers of endothelial dysfunction in the RUPP rat. Moreover, we have more recently shown that PIBF lowers blood pressure in the RUPP rat model of PE. This study was designed to test two hypothesis. We first wanted to determine a role for sFlt‐1 to cause mt dysfunction and ROS during pregnancy. We next hypothesized the PIBF supplementation would lower in sFlt‐1 induced hypertension during pregnancy and improve mt function in response to sFlt‐1 during pregnancy. sFlt‐1 was infused into normal pregnant (NP) Sprague‐Dawley rats (3.7 μg·kg−1·day−1 for 6 days, gestation days 13–19) in the presence or absence of PIBF (2.0 μg/mL) administered intraperitoneal on GD 15 to normal pregnant (NP) rats. Mean arterial blood pressure (MAP) and placental mt ROS were measured on GD 19. Infusion of sFlt‐1 into NP rats increased MAP 112 ±2 (n=11) compared with control NP rats 98±2 mmHg (n=15, p<0.05). Administration of PIBF reduced MAP to 100±1 mmHg in the presence of sFlt‐1 (n=5, p<0.05). Mt ROS in placenta was 108±6 in NP (n=4), 429±32 in NP+ sFlt‐1 (n=3, p<0.05), and significantly reduced to 234±15 in NP+ sFlt‐1+ PIBF (n=3, p<0.05). State 3 respiration, which is indicative of ATP production, was reduced in placentas of sFlt‐1 infused rats versus NP, but was improved with PIBF. Overall, our study implicates a role for sFlt‐1 to reduce placental mt function during pregnancy and that supplementation of PIBF improved placental mt function which was associated with improved blood pressures. Our data indicate the importance of improved progesterone signaling to restore placental function in the presence of sFlt‐1 which led to improved hypertension and therefore should be considered a potential therapeutic for PE.Support or Funding InformationNIH Grants: RO1HD067541‐06 and P20GM121334; T32HL105324