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17‐Hydroxyprogesterone caproate improves fetal growth restriction possibly by reducing inflammation and placental cytolytic NK cells in response to placental ischemia during pregnancy
Author(s) -
Amaral Lorena Machado,
Elfarra Jamil,
Cornelius Denise C,
Cunningham Mark W,
LaMarca Babbette
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1011.24
Subject(s) - medicine , preeclampsia , uterine artery , endocrinology , fetus , placental growth factor , ischemia , intrauterine growth restriction , gestation , pregnancy , vascular endothelial growth factor , biology , genetics , vegf receptors
Preeclampsia (PE), new onset hypertension, is characterized by elevated tumor necrosis factor (TNF‐α), anti‐angiogenic factor soluble fms‐like tyrosine kinase (sFlt‐1), natural killer (NK) cells, oxidative stress and placental ischemia predicted with increased uterine artery resistance (UARI). These contributing factors are likely contributors to the decreased fetal weight during PE pregnancies. Cytolytic NK are an important arm of the immune system killing tumors and infected cells by perforin‐granzyme‐mediated cytolysis which have been shown to be increased in PE women compared to normal pregnancy. Currently, there is no effective treatment for PE except for early delivery, making PE the leading cause for premature births worldwide. Administration of 17‐hydroxyprogesterone caproate (17‐OHPC) is approved for cessation of preterm labor in pregnancies not complicated by PE. The objective of this study was determine whether early administration of 17‐OHPC could improve pregnancy outcomes in response to placental ischemia. To do so, 17‐OHPC (3.32mg/kg) was administered intraperitoneally on gestation day 15 to reduced uterine perfusion pressure (RUPP) rats. UARI was measured using Doppler ultrasound and carotid catheters were inserted on day 18. Blood pressure (MAP), nitric oxide (NO), placental cytolytic NK cells and perforin‐grazyme levels were measured on GD 19. MAP in normal pregnant (NP) rats (n=12) was 94 ± 2, 126 ± 2 in RUPP (n=27) and 111±1 mmHg in RUPP+17‐OHPC (n=15), p<0.05. Pup weight was 2.3±0.09 in NP, 1.9± 0.04 in RUPP rats, which improved to 2.1±0.06 grams in RUPP+17‐OHPC p<0.05. UARI was 0.6±0.01 in NP (n=3), 0.8±0.03 in RUPP rats (n=4), which improved to 0.6±0.04 in RUPP+17‐OHPC (n=5), p<0.05. Total number of placental NK cells was 8.6 ± 3.1 in NP (n=3), 20.2 ±2.4 in RUPP rats (n=6), which decreased to 1.6 ± 0.54 % in RUPP+17‐OHPC (n=5), p<0.05. Activated placental NK cells was 3.8 ± 2.2 in NP (n=3), 11.9±2.01 in RUPP (n=6), which improved to 0.4 ± 0.2 % in RUPP+17‐OHPC (n=5), p<0.05. Perforin‐granzymes were 0.04±0.001, 0.004±0.001 in RUPP (n=4), which improved to 0.02±0.003, 0.0008±0.0001 pg/ug protein in RUPP+17‐OHPC (n=6), p <0.05. Plasma NOx was 22.9±1.6 in NP (n=9), 10.82±2.3 in RUPP rats (n=13) which improved to 25.5±5.2 μM in RUPP+17‐OHPC (n=5), p<0.05. Administration of 17‐OHPC improves UARI, NO bioavailability, activated cytolytic NK cells, perforin‐grazymes, pup weight, and hypertension in response to placental ischemia indicating the potential benefit of 17‐OHPC to improve NK cell modulated pathogenicity and pregnancy outcomes associated with PE. Support or Funding Information NIH grants RO1HD067541‐06, T32HL105324