Novel biomarker profiles in experimental aged maternal mice with hypertensive disorders of pregnancy

Recently, advanced maternal age (AMA) has increased in Western countries because of late marriage and advances in assisted reproductive technology. One major complication of AMA is hypertensive disorders of pregnancy (HDP). While clinical investigations into human AMA have been reported, there has been limited information obtained from basic research. In this investigation, we established the AMA mouse model using aged pregnant ICR mice. We demonstrated that the phenotypes of aged pregnant ICR mice reflect the same characteristics as human AMA. The significant findings of our investigation are as follows: (1) The AMA mouse model manifested the same complication phenotypes of human AMA, including maternal obesity, declining fertility, small for gestational age, and a higher rate of intrauterine fetal death; (2) The AMA mouse model exhibited an increasing systolic blood pressure at late gestation (108.2 ± 7.7 vs. 92.7 ± 5.7 mmHg, P < 0.01) that normalized after delivery similar to human HDP patients; and (3) While HDP and placental dysfunction are complicated, AMA mice and human HDP AMA patients manifested a low serum soluble fms-like tyrosine kinase-1 (sFlt-1) level in late gestation (AMA group vs. control group, mice, 16800.0 ± 10709.5 vs. 26611.9 ± 8702.0 pg/mL, respectively, P < 0.01; human, 8507.6 ± 3298.7 vs. 14816.9 ± 5413.5 pg/mL, respectively, P < 0.05). In conclusion, the aged pregnant mouse model resembled human AMA. The AMA mouse model was complicated with HDP despite the low serum sFlt-1 level. Our findings provide evidence that the serum sFlt-1 level does not necessarily reflect the conventional pathogenesis of HDP in aged human and murine pregnancies and may contribute to the future management of HDP in AMA.