Natural killer cells mediate pathophysiology in response to reduced uterine perfusion pressure

Abstract

Preeclampsia is associated with hypertension, small-for-gestational-age babies, and increased cytolytic natural killer (NK) cells. The specific role of cytolytic NK cells in the pathophysiology of preeclampsia has not been clearly defined. We hypothesized that Reduced Uterine Perfusion Pressure (RUPP) stimulates proliferation and cytolytic activation of NK cells, and that reducing NK cells in RUPP would prevent hypertension, intrauterine growth restriction, and inflammation in response to placental ischemia. RUPP was induced on gestation day (GD) 14 in pregnant rats. NK cells were depleted by i.p. administration of anti-asialo GM1 antibody on GDs 15 and 17. Placental and circulating NK cells were quantified via flow cytometry, mean arterial pressure (MAP), fetal weights, and cytokines were measured on GD 19. Total placental NK cells were 7.4±2% of gated cells in normal pregnant (NP; n=10) and 16.5± 3% of gated cells in RUPP (n=10) rats. Furthermore, cytolytic placental NK cells also increased in RUPP. Depletion of NK cells in RUPP (RUPP + anti-ASGM1) significantly improved MAP and fetal weights. MAP was 108± 2 mmHg in NP, 125± 2 mmHg in RUPP, and 112± 2 mmHg in RUPP + anti-ASGM1 (n=12). Fetal weight was 2.32 ± 0.05 in NP, 1.8± 0.04g in RUPP, and increased to 2.0± 0.04g in RUPP + anti-ASGM1. Placental interferon-γ (IFN-γ) was 40.4± 5.2 pg/mg in NP, 72.17± 3.2 pg/mg in RUPP, and 44.0± 6.5 pg/mg in RUPP + anti-ASGM1 (P<0.05). Placental tumor necrosis factor-α (TNF-α) was 17.9± 1.7 pg/mg in NP, 23.9± 2.2 pg/mg in RUPP, and 12.9± 2.3 pg/mg in RUPP + anti-ASGM1 (P<0.05). Depletion of NK cells significantly lowered MAP, intrauterine growth restriction, and inflammation in RUPP rats indicating that cytolytic NK cells are important in preeclampsia pathophysiology.

Chronic infusion of interleukin‐17 promotes hypertension, activation of cytolytic natural killer cells, and vascular dysfunction in pregnant rats

“…Additionally, NK depletion improved maternal and fetal outcomes indicating that this activation contributed to the preeclamptic phenotype (Elfarra et al. ). We next performed an adoptive transfer of RUPP stimulated T H 17 cells into normal pregnant animals and saw increased NK cell proliferation and production of cytolytic enzymes.…”

“…Our group has previously demonstrated that depletion of NK cells in the RUPP model improves both maternal and fetal outcomes (Elfarra et al. ). In addition, we have shown that adoptive transfer of RUPP stimulated T H 17 cells into normal pregnant animals induces a preeclamptic phenotype and results in significantly increased cNK cell populations (Cornelius et al.…”

Hypertension in pregnancy: Taking cues from pathophysiology for clinical practice

“…A reduced uterine perfusion pressure rat model led to the conversion of tolerogenic dNKs to a cytolytic phenotype. This shift was associated with higher mean arterial pressure, fetal intrauterine growth restriction (FUGR), and increased inflammation, changes that were reversed by the depletion of NK cells …”

“…Risk factors for preeclampsia 2 pressure rat model led to the conversion of tolerogenic dNKs to a cytolytic phenotype. This shift was associated with higher mean arterial pressure, fetal intrauterine growth restriction (FUGR), and increased inflammation, changes that were reversed by the depletion of NK cells 15. 4.2 | Inadequate remodeling of spiral uterine arteries by cytotrophoblast cellsThe first observations of SUA remodeling in pregnancy came from placental biopsy specimens acquired during cesarean sections.…”

The role of immunity in the pathogenesis and development of pre‐eclampsia

“…A rodent experiment demonstrated that an increase in cytolytic NK cells in PE is directly related to high blood pressure and foetal uterine growth restriction. The study found that RUPP induced the activation and proliferation of cytolytic NK cells in mice and that the depletion of NK cells in mice prevented placental ischaemia induced high blood pressure, intrauterine growth restriction and inflammation …”