Natural Killer Cells Stimulated in Response to Placental Ischemia Mediate Hypertension, Intrauterine Growth Restriction, and Inflammation during Pregnancy
Authors: Cornelius Denise C , McCalmon Maggie , Amaral Lorena M , Elfarra Jamil , Cunningham Mark W , Ibrahim Tarek , Scott Jeremy D , LaMarca Babbette 
Published: November 2023

Women with preeclampsia (PE), newly developed hypertension and renal dysfunction during pregnancy, have small‐for‐gestational‐age babies and demonstrate an increase in the cytolytic natural killer (NK) cell activation. The specific role of cytolytic NK cells in the pathophysiology of PE has not been clearly defined. The reduced uterine perfusion pressure (RUPP) model of placental ischemia (PI) exhibits many of the characteristics of PE including hypertension, renal dysfunction, chronic inflammation and intrauterine growth restriction (IUGR). In this study, we tested the hypothesis that PI results in cytolytic activation of NK cells, and examined a role for a reduction in NK cells in RUPP to attenuate PE‐like characteristics in response to PI. In this study NK cells were depleted in RUPP rats by intraperitoneal administration of the Anti‐asialo GM1 antibody on gestation days 15 and 17. PBMCs and placental lymphocytes were examined via flow cytometry to quantify cytolytic NK cells and to verify NK cell depletion, blood pressure (MAP) and pup weights were measured. Total placental NK cells numbers significantly increased in response to PI (NP: 7.4±2% (n=10); RUPP: 16.5±3% (n=10)), as well as cytolytic activation of placental NK cells in response to PI (NP: 3.0±0.96% vs RUPP: 11.7±3.5%, p<0.05). Circulating total and cytolytic NK cells followed a similar trend. Moreover, depletion of NK cells in RUPP (total NK: RUPP: 14.3±3.8% vs RUPP+NKD: 3.5±0.9%) significantly improved blood pressure and intrauterine growth restriction (IUGR): MAP significantly increased in response to PI from 109.5±2.3 mmHg in NP (n=10) to 125.4±2.7 mmHg (n=9) in RUPP rats (p<0.001). Depletion of NK cells with the cell specific depleting antibody significantly lowered blood pressure to 111.8.±2 mmHg in RUPP+NKD rats (n=12, p<0.01). Additionally, NK cell depletion in RUPP significantly reduced IUGR in response to PI (1.8±0.04g in RUPP vs. 2.0±0.4g in RUPP+NKD; p<0.05). Placental inflammatory cytokines were attenuated with depletion of NK cells in RUPP rats: Placental IFN‐γ: NP (n=7)−40.4±5.2 pg/ml/mg; RUPP (n=4)−72.17±3.2 pg/ml/mg; RUPP+NKD (n=6)−44.02±6.5 pg/mg/mL p<0.05 vs RUPP; Placental TNF‐α: NP (n=6)−17.9±1.7 pg/ml/mg; RUPP (n=5)−23.9±2.2 pg/ml/mg; RUPP+NKD (n=6)−12.9±2.3 pg/ml/mg p<0.05 vs RUPP. Circulating inflammation followed a similar trend: Serum IFN‐γ: NP (n=6)−2.9±2 pg/ml; RUPP (n=4)−132.3±47 pg/mL; RUPP+NKD (n=6)−138.7±35 pg/mL n.s. vs RUPP; serum TNF‐α NP (n=7)−11.3±4 pg/mL; RUPP (n=6)−45.7±9 pg/mL; RUPP+NKD (n=6)−10.9±4 pg/ml p<0.01 vs RUPP. Depletion of NK cells in RUPP rats was positively associated with lowering blood pressure and blunting IUGR and inflammation in response to PI. These results suggest a role for cytolytic NK cells in contributing to hypertension, IUGR, and inflammation in response to PI, potentially identifying previously unknown mechanisms of PE pathophysiology and new therapeutic targets to improve maternal and fetal outcomes of PE.Support or Funding InformationAmerican Heart Association 16SDG27520000National Institutes of Health 1K99HL130456, R01HD067541, F32HL126301