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). Progesterone induced blocking factor (PIBF) is a product of progesterone signaling that blocks inflammatory processes and we have previously shown PIBF to lower mean arterial blood pressure (MAP) and sFlt-1 in a rat model of PE. Infusion of sFlt-1 causes hypertension and many characteristics of PE in pregnant rodents, however, its role in causing mt dysfunction is unknown. Therefore, we hypothesize that PIBF will improve mt function and MAP in response to elevated sFlt-1 during pregnancy. We tested our hypothesis by infusing sFlt-1 via miniosmotic pumps in normal pregnant (NP) Sprague-Dawley rats (3.7 μg·kg−1·day−1) on gestation days (GD) 13–19 in the presence or absence of PIBF (2.0 µg/mL) injected intraperitoneally on GD 15 and examined mean arterial blood pressure (MAP) and placental mt ROS on GD 19. sFlt-1 increased MAP to 112 + 2 (n = 11) compared to NP rats (98 + 2 mmHg, n = 15, p < 0.05), which was lowered in the presence of sFlt-1 (100 + 1 mmHg, n = 5, p < 0.05). Placental mtATP was reduced in sFlt-1 infused rats versus NP controls, but was improved with PIBF. Placental mtROS was elevated with sFlt-1 compared to NP controls, but was reduced with PIBF. Sera from NP + sFlt-1 increased endothelial cell mtROS, which was attenuated with PIBF. These data demonstrate sFlt-1 induced HTN during pregnancy reduces placental mt function. Importantly, PIBF improved placental mt function and HTN, indicating the efficacy of improved progesterone signaling as potential therapeutics for PE.

A 26-year-old woman who had been taking an oral contraceptive preparation for two years Zacherle and Richardson (I972) described a case in which severe hypertension developed while the patient was on oral contraceptives. Antihypertensive agents controlled the blood pressure satisfactorily and the blood pressure remained normal after withdrawal of all therapy. Reintroduction of a sequential oral contraceptive agent 3 years later again resulted in severe hypertension associated on this occasion with early hypertensive retinopathy and irreversible renal failure. Harris (I969) described a case of malignant hypertension associated with oral contraceptive therapy. The patient had never been pregnant nor was there a family history of hypertension. After one year on antihypertensive therapy, the patient developed symptoms of postural hypotension. Therapy was discontinued and the patient's blood pressure subsequently remained normal. So far as we are aware, there have been no other reports showing an association between malignant hypertension and oral contraceptive agents.Case report A 26-year-old woman presented in June I966 with an 8-month history of increasing dyspnoea, a 3-month history of headaches, and two episodes of vomiting in the preceding week. During her second pregnancy in I960 she had developed hypertension, but her blood pressure had settled to normal levels post partum, and investigation had failed to reveal a cause for her hypertension. In I964, the patient had been started on the oral contraceptive agent 'Anovlar 2I' (norethisterone acetate 4 mg and ethinyl oestradiol o.os mg) by her general practitioner. She remained on this therapy until the time of admission when her blood pressure was 230/I50 mmHg (3I/20 kPa). Fundi showed papilloedema, haemorrhages, exudates, and hypertensive vessel changes. She was moderately obese.Blood urea was 33 mg/Ioo ml (5 mmol/l). Plasma sodium was I36 mmol/l. and chloride was 103 mmol/l. Plasma potassium on admission was low, being 2.7 mmol/l, but repeat estimations were normal at 3.9 mmol/l and 4.2 mmol/l. Creatinine clearance was 70 ml/min. There was proteinuria, but mid-stream specimens of urine contained no cells or casts and there

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 Information NIH Grants: RO1HD067541‐06 and P20GM121334; T32HL105324

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 other characteristics of PE in pregnant rodents. 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 which lowers inflammatory processes. We have shown that PIBF lowers blood pressure in a rat models of PE. This study was designed not only examine the role of mt ROS in sFlt-1 induced hypertension during pregnancy but to also examine the effect of PIBF to improve mt function and hypertension in response to elevated 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 (GD) 13-19 ) in the presence or absence of PIBF (2.0 μg/mL) administered intraperitoneal on GD 15 to sFlt-1 induced hypertensive pregnant rats. Mean arterial blood pressure (MAP), placental and endothelial mt ROS and function were measured on GD 19. Infusion of sFlt-1 into NP rats increased MAP to 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) and reduced to 234 + 15 in NP+ sFlt-1+ PIBF (n=3). 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. Moreover, sera from NP+sFlt-1 treated with PIBF attenuated endothelial cell mtROS ( 29 + 8 % gate) compared with sera from NP+sFlt-1 (54 + 15 % gate (n=4)). Our study indicates a role of sFlt-1 induced hypertension during pregnancy to reduce placental and endothelial cell mt function. Importantly, supplementation of PIBF improved mt function and ROS which was associated with improved blood pressure in sFlt-1 induced hypertensive pregnant rats indicating the efficacy of improved progesterone signaling as a potential therapeutic for PE.