Assessment of Hypoxia-Related Markers in the Maternal-fetal Interface in the BPH/5 Mouse Model of Preeclampsia at High Altitude

Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by abnormal placental development, and maternal/fetal morbidity and mortality. Despite affecting approximately 10% of pregnancies globally the exact pathophysiology remains unknown. High altitude is a significant risk factor for PE. The Blood Pressure High/5 (BPH/5) genetic mouse strain spontaneously develops PE-like symptoms and exhibits elevated inflammatory and hypoxia markers during early gestation at sea level. Previous studies have demonstrated that BPH/5 mice display increased expression of hypoxia-inducible factor 1 alpha (Hif1α) and its downstream targets at embryonic day (e) 7.5 when housed at low altitude (46 ft). However, the impact of high altitude (>5,000 ft) on this established model remains unknown. This study aims to determine if decidual inflammatory and hypoxic markers in BPH/5 are altered by high-altitude conditions. We tested the hypothesis that hypoxia-related gene expression (Hif1α, heme oxygenase-1 [Ho-1], vascular endothelial growth factor [VEGF], prostaglandin synthase 2 [Ptgs2], and tumor necrosis factor-alpha [TNFα]) in BPH/5 mice maintained at high altitude will not differ significantly from BPH/5 mice at low altitude, despite the change in environmental oxygen levels. Intrastrain timed matings were established using adult (8-12 weeks of age) female and male BPH/5 and C57 mice. The day of copulatory plug, detection is denoted as e0.5. Implantation sites were collected at e7.5 and snap-frozen for molecular analyses from high-altitude BPH/5 (BPH5-HA), low-altitude BPH/5 (BPH5-LA), and control C57 mice maintained at low altitude (n=6). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis using SYBR green after RNA isolation and cDNA synthesis was performed in triplicate to assess relative mRNA expression of target genes compared to a housekeeper gene, 18S rRNA. Statistical analyses were performed using a one-way ANOVA and significance set at p<0.05. Our data revealed a 2-fold increase in TNFα (p=0.0026) and Hif1α (p=0.0001) mRNA levels in BPH5-HA compared to BPH5-LA mice, while Ho-1 expression was significantly decreased by 50% (p=0.0175). VEGF and Ptgs2 mRNA levels remained unchanged. These results demonstrate that high altitude exposure significantly alters the expression of key hypoxia-related genes in BPH/5 mice during early pregnancy, suggesting potential maladaptation to increased altitude. Further investigation of these alterations may provide important insights into the relationship between altitude and PE pathophysiology. National Institute of Health (R01HD114145) 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.