ABSTRACT
Preeclampsia (PE) is characterized by new-onset hypertension in association with elevated natural killer (NK) cells and inflammatory cytokines, which are likely culprits for decreased fetal weight during PE pregnancies. As progesterone increases during normal pregnancy, it stimulates progesterone-induced blocking factor (PIBF). PIBF has been shown to decrease inflammation and cytolytic NK cells, both of which are increased during PE. We hypothesized that PIBF reduces inflammation as a mechanism to improve hypertension in the preclinical reduced uterine perfusion pressure (RUPP) rat model of PE. PIBF (2.0 µg/mL) was administered intraperitoneally on gestational day 15 to either RUPP or normal pregnant (NP) rats. On day 18, carotid catheters were inserted. Mean arterial blood pressure (MAP) and samples were collected on day 19. MAP in NP rats (n = 11) was 100 ± 2 mmHg and 105 ± 3 mmHg in NP + PIBF rats (n = 8) and 122 ± 1 mmHg in RUPP rats (n = 10), which improved to 110 ± 2 mmHg in RUPP + PIBF rats (n = 11), P < 0.05. Pup weight was 2.4 ± 0.1 g in NP, 2.5 ± 0.1 g in NP + PIBF, 1.9 ± 0.1 g in RUPP, and improved to 2.1 ± 0.1 g in RUPP + PIBF rats. Circulating and placental cytolytic NK cells, IL-17, and IL-6 were significantly reduced while IL-4 and T helper (TH) 2 cells were significantly increased in RUPP rats after PIBF administration. Importantly, vasoactive pathways preproendothelin-1, nitric oxide, and soluble fms-Like tyrosine Kinase-1 (sFlt-1) were normalized in RUPP + PIBF rats compared with RUPP rats, P < 0.05. Our findings suggest that PIBF normalized IL-4/TH2 cells, which was associated with improved inflammation, fetal growth restriction, and blood pressure in the RUPP rat model of PE.
Subject(s)
Antigens, Neoplasm/pharmacology , Blood Pressure/physiology , Inflammation/drug therapy , Progesterone/pharmacology , Uterus/drug effects , Animals , Cytokines/metabolism , Female , Fetal Growth Retardation/physiopathology , Fetus/drug effects , Fetus/metabolism , Hypertension/chemically induced , Hypertension/physiopathology , Inflammation/chemically induced , Inflammation/metabolism , Ischemia/physiopathology , Killer Cells, Natural/metabolism , Placenta/metabolism , Pregnancy , Rats , Uterine Artery/drug effects , Uterine Artery/physiopathology , Uterus/physiopathologyABSTRACT
Preeclampsia (PE) is characterized by new onset hypertension in association with elevated soluble fms-like tyrosine kinase-1 (sFlt-1) and preproendothelin-1 (PPET-1) levels. Currently there is no effective treatment for PE except for early delivery of the fetal placental unit, making PE a leading cause for premature births worldwide. Administration of 17-hydroxyprogesterone caproate (17-OHPC) is used for prevention of recurrent preterm birth. This study was designed to test the hypothesis that 17-OHPC improves hypertension and ET-1 in response to elevated sFlt-1 in pregnant rats. 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 17-OHPC (3.32 mg/kg) administered via intraperitoneal injection on gestational days 15 and 18. Mean arterial blood pressure (MAP), pup and placenta weights, renal cortex PPET-1 mRNA levels and nitrate-nitrite levels were measured on GD 19. Infusion of sFlt-1 into NP rats elevated mean arterial pressure (MAP) compared with control NP rats: 115 ± 1 (n = 13) vs. 99 ± 2 mmHg (n = 12, p < 0.05). 17-OHPC attenuated this hypertension reducing MAP to 102 ± 3 mmHg in sFlt-1 treated pregnant rats (n = 8). Neither pup nor placental weight was affected by sFlt-1 or 17-OHPC. Importantly, renal cortex PPET-1 mRNA levels were elevated 3 fold in NP + sFlt-1 rats compare to NP rats, which decreased with 17-OHPC administration. Plasma nitrate-nitrite levels were 44 ± 9 µM in NP rats (n = 9), 20 ± 3 µM in NP + sFlt-1 (n = 7), which increased to 42 ± 11 µM NP + sFlt-1 + 17OHPC (n = 6). Administration of 17-OHPC improves clinical characteristics of preeclampsia in response to elevated sFlt-1 during pregnancy.
