Maternal B Cell Depletion Reduces Blood Pressure and Improves Fetal Weights in Male Offspring of a Rat Model of Preeclampsia
Authors: Campbell Nathan , Herrock Owen , Fitzgerald Sarah , Solise Dylan , Turner Ty , Deer Evangeline , Amaral Lorena , Alexander Barbara , LaMarca Babbette 
Published: May 2022

Preeclampsia (PE), new onset hypertension during pregnancy, is the leading cause of death and morbidity for the mother and low birth weight in offspring. Low birth weight has been shown to cause offspring to be at high risk for cardiovascular and metabolic disorders later in life. PE has been associated with chronic immune activation including T helper cells and natural killer cells. PE women also have activated B cells producing agonistic autoantibodies to the angiotensin II type I receptor (AT1‐AA). AT1‐AA has been implicated in numerous pathways in the pathophysiology of PE. We have shown Rituximab (R), used clinically for B cell depletion, lowers mean arterial pressure (MAP), B cells, and AT1‐AA in the reduced uterine perfusion pressure (RUPP) rat model of PE. Clinical studies show no untoward effects on offspring of pregnant women maintained on R for treating lymphoma. R is not used during PE, therefore, effects of maternal B cell depletion on offspring survival and growth in response to placental ischemia is unknown. We hypothesize that R will deplete maternal B cells in RUPP rats without worsening the effect of placental ischemia on pup growth and survival. To test this hypothesis, the RUPP procedure was performed and R (250 mcg/kg) was given on gestation day (GD) 14 via mini‐osmotic pump. On GD 19, B cells were measured by flow cytometry, and MAP and pup weights were recorded. A separate group of dams were allowed to deliver, pup weights were recorded within 12 hours of birth and weekly until 16 weeks, and B cells were analyzed. A one‐way or two‐way ANOVA was used for statistical analysis. MAP increased in RUPP 123±2 (n=19, p<0.05) compared to NP controls 101±1 (n=18) and was 106±3 mmHg in RUPP+R (n=8, p<0.05). On GD19, maternal circulating B cells were 16±2 % (n=14) in RUPPs, 8±2 % in NP rats, (n=7, p<0.05), and 5.5±1% gate in RUPP+R (n=5, p<0.05). RUPP male and female offspring tended to be smaller (5.11±0.23 g, 5.19±0.14 g; n=4, n=4) at birth than NP offspring (6.09±0.15 g, 5.87±0.12 g; n=6, p<0.064; n=6, p<0.948) or RUPP+R offspring (5.75±0.24 g, 5.36±0.28 g; n=6, p=0.291; n=6, p>0.999). At 12 weeks, male and female RUPP offspring had elevated circulating B cells (21.24±2.92, 20.04±0.72 %; n=6; n=9) compared to NP (1.38±0.23, 1.63±0.06 %; n=4, p<0.05; n=3, p<0.04) which was normalized in RUPP+R offspring (0.40±0.10, 0.27±0.03 % gate; n=3, p<0.05; n=8, p<0.05). At 16 weeks, B cells were comparable in male and female offspring from NP (0.78±0.09 %, n=10; 1.06±0.21 % gate, n=6) and RUPP+R rats (1.21±0.34% gate, n=5; 1.62±0.34% gate, n=5), but were elevated in RUPP male and female offspring (2.45±0.27% gate, n=9; 1.68±0.45% gate, n=13) compared to NP (p<0.05; p>0.99) and RUPP+R (p<0.05; p>0.99). Our findings indicate that R lowers maternal circulating B cells and MAP in RUPP rats and improves fetal weight and circulating B cells, indicating that R does not worsen adverse fetal outcomes in response to placental ischemia.