Perinatal TNF-α Blockade in a Rat Model of Preeclampsia Exhibits Sex Specific Outcomes in Adult Offspring

Preeclampsia (PE), new-onset hypertension during pregnancy in association with other-organ dysfunction including the placenta. It is associated with inflammatory cytokines and fetal growth restriction (FGR) which itself is associated with increased risk for hypertension and cardiovascular disease in adult offspring. PE women have increased tumor necrosis factor alpha (TNF-α) and agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA). Moreover, female PE children are at elevated risk for PE during pregnancy indicating a familial connection with PE. The reduced uterine perfusion pressure (RUPP) model of PE recaptures many of the characteristics of PE including hypertension, inflammatory activation, and fetal growth restriction. Growth-restricted RUPP offspring develop hypertension as adults and we have recently shown that adult RUPP offspring also produce AT1-AA. Importantly, RUPP rats have increased TNF-α and we have shown that TNF-α blockade with etanercept improves maternal blood pressure. The use of etanercept has not resulted in negative effects for mothers with autoimmune disorders that are kept on their treatment throughout pregnancy, however, its effect on fetal weight and long-term health is still being investigated. We hypothesize that etanercept could improve cardiovascular and chronic inflammatory outcomes in adult RUPP offspring. Pregnant rats were divided into the following groups: Sham, Sham + Etanercept, RUPP, RUPP + Etanercept. RUPP surgeries were performed on gestational day 14 and Etanercept (400 mcg/kg) was injected i.p. on gestational day 18. The dams were allowed to deliver naturally and birth weights were recorded within 12 hours. At 4 months of age mean arterial pressure (MAP) was recorded via carotid catheters, and blood and tissues were collected. Immune cells were measured by flow cytometry. AT1-AA was measured using a cardiomyocyte bioassay. A two-way ANOVA was used for statistical analysis. Etanercept improves birth weight in male RUPP offspring (5.2±0.2 g, n=7 (RUPP) vs 6.0±0.3g, n=9, p<0.05 (RUPP+Etanercept)), but did not affect adult blood pressure or inflammatory factors. Although Etanercept did not improve female birth weight, Etanercept trended to improve MAP in RUPP female offspring (130±5 mmHg, n=6, (RUPP) vs 123±4 mmHg, n=7 (RUPP+Etanercept)). In addition, there was a trending decrease in circulating B cells in the RUPP female offspring compared to sham female offspring which was normalized in the RUPP + Etanercept female offspring. (4.24±0.81 % gated, n=5 (RUPP); vs 9.56±2.07 % gated, n=7 (Sham), vs 9.04±1.42 % gated, n=6, (RUPP+Etanercept)). RUPP + Etanercept female offspring also had decreased in circulating AT1-AA which was elevated in RUPP female offspring (16±3 ΔBPM (RUPP), n=5, 7±2 ΔBPM, n=4 (RUPP+Etanercept), -1±2 ΔBPM, n=5, (Sham)). Overall, perinatal Etanercept treatment did not worsen fetal outcomes. Importantly, Etanercept may have a more positive effect to improve overall health outcomes of female offspring as seen by the trend to reduce blood pressure, normalize immune cells, and reduce circulating AT1-AA in adult females. Blocking TNF-α during PE may be a potential therapeutic strategy to improve both maternal and female fetal outcomes. This study was supported by NIH grants R01HL170622 (BL), R01HL143459 (BTA), F31HD110230 (NC), P20GM104357 (BTA), P30GM149404 (BTA), and P20GM121334 (BL, BTA). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.