(141) Preeclampsia-like features induced by reduced uteroplacental perfusion in a transgenic mouse model of Alzheimer’s disease

Animal models that recapitulate preeclampsia (PE)-like features can greatly facilitate studies of PE mechanism. One such model, the reduced uteroplacental perfusion pressure (RUPP), was originally optimized in Sprague-Dawley rats. However, the advancement of genetically modified mice has led researchers to search for murine models where relationships between genes and disease phenotypes can be specifically studied. We aimed to optimize the RUPP procedure in 5xFAD^+/-/APOE-TR^+/+ (EFAD) mice, a humanized transgenic mouse model of Alzheimer’s disease and to compare the presence and severity of PE-like features to wild-type (WT) mice.

Study Design:

2-4 month old timed pregnant WT and EFAD C57/BL6J mice underwent RUPP on (GD)13.5 by bilateral ligation of ovarian vessels. Animals were sacrificed on GD17.5, for tissue harvest and assessment of PE endpoints: mean arterial pressure (MAP), albumin/creatinine ratio, serum sFlt-1/PlGF-2 ratio, kidney and placental morphology, fetal weights and placental efficiency (placental/fetal weight ratio). Pilot experiments assessing PE endpoints on GD18.5 resulted in fetal death of ~60% of RUPP mice. Control mice underwent sham procedures where ovarian vessels were not ligated. Data from n=6-13 mice per group was tested for normality and analyzed by parametric statistics.

Results:

1) RUPP resulted in a significant increase in MAP in WT (p=0.006) but not in EFAD mice; 2) RUPP did not increase the albumin/creatinine or sFlt-1/PlGF-2 ratios in either WT or EFAD mice; 3) RUPP mice had discernable changes in kidney morphology consistent with kidney injury independent of genotype; 4) RUPP decreased placental efficiency in EFAD (p=0.003) but not in WT mice.

Conclusion: The extent to which RUPP mimics different PE-endpoints varies with mouse genetic background. Unlike WT mice, EFAD mice remain normotensive following RUPP, yet they have increased susceptibility to placental insufficiency; an observation with relevance to the heterogeneity of clinical manifestations comprising the PE syndrome.