17-Hydroxyprogesterone caproate improves T cells and NK cells in response to placental ischemia; new mechanisms of action for an old drug

Preeclampsia (PE) is new onset hypertension during pregnancy associated with increased uterine artery resistance (UARI) and an imbalance among CD4 + T lymphocytes and natural killer (NK) cells. We have shown an important role for 17-hydroxyprogesterone caproate (17-OHPC) to improve hypertension and fetal demise in the RUPP rat model of PE. However we have not examined a role for 17-OHPC to improve NK cells and CD4+TH2 cells as possible mechanisms for improved fetal weight and hypertension. Therefore, we hypothesized that 17-OHPC lowers NK cells while improving the T cell ratio in the RUPP rat. RUPP was surgically induced on gestational day 14 in pregnant rats. 17-OHPC (3.32 mg/kg) was administered intraperitoneal on day 15, UARI was measured on day 18. Blood pressure (MAP), blood and tissues were collected on GD 19. MAP in NP rats (n = 9) was 100 ± 2, 104 ± 6 in Sham rats (n = 8), 128 ± 2 in RUPP (n = 11) and 115 ± 3 mmHg in RUPP + 17-OHPC (n = 10), p < 0.05. Pup weight and UARI were improved after 17-OHPC. Total and cytolytic placental NK cells were 38 ± 5, and 12 ± 2% gate in RUPP rats which decreased to 1.6 ± 0.5 and 0.4 ± 0.2% gate in RUPP + 17OHPC rats. CD4+ T cells were 40 ± 3 in RUPP rats, which significantly decreased to 7 ± 1 RUPP + 17-OHPC rats. Circulating and placental TH2 cells were 6.0 ± 1, 0.3 ± 0.1% gate in RUPP rats and 12 ± 1%, 2 ± 0.5% gate in RUPP + 17-OHPC rats, p < 0.05 This study identifies new mechanisms whereby 17-OHPC improves outcomes in response to placental ischemia.