Placenta–Brain Axis Disruption in Maternal Preeclampsia: Stereological and Spatial Neurovascular Mapping of Fetal Hippocampal Development

Background: Preeclampsia (PE) is a multisystem hypertensive disorder of pregnancy that imposes far-reaching consequences on fetal neurodevelopment through disruption of the placenta–brain axis. While clinical associations between maternal PE and offspring neurocognitive impairment are well documented, the precise structural and vascular alterations within the fetal hippocampus remain incompletely characterised. Objectives: To quantify stereological parameters—including neuronal number, synaptic density, and glial cell populations—within the fetal hippocampus following maternal PE, and to perform three-dimensional spatial mapping of neurovascular unit integrity across hippocampal subfields. Methods: A validated rat model of PE was induced via continuous systemic administration of Nω-nitro-L-arginine methyl ester (L-NAME) from gestational day (GD) 14 to GD 20. Fetal brains were harvested at GD 20 and postnatal day (PND) 21. Stereological analyses employed the optical fractionator and Cavalieri principle. Spatial neurovascular mapping integrated confocal immunofluorescence of RECA-1, aquaporin-4 (AQP4), platelet-derived growth factor receptor-β (PDGFRβ), and synaptophysin. Placental transcriptomics (RNA-sequencing) and fetal serum cytokine profiling complemented the morphological data. Results: PE dams exhibited significantly elevated systolic blood pressure (163 ± 8 vs. 112 ± 6 mmHg; p < 0.001) with marked proteinuria. Fetal hippocampal pyramidal neuron count was reduced by 34.7% in CA1 and 28.3% in CA3 relative to controls (p < 0.01). Dentate gyrus granule cell density declined by 22.1% (p < 0.05). Synaptophysin immunoreactivity fell by 41.6% in stratum radiatum. Microvessel density decreased 38.9% and pericyte coverage declined 46.2%. AQP4 polarisation at astrocytic endfeet was significantly disrupted. Placental sFlt-1 transcripts were upregulated 5.8-fold; fetal serum IL-6, TNF-α, and VEGF were reciprocally altered. Conclusions: Maternal PE induces a reproducible syndrome of hippocampal hypoplasia, synaptic rarefaction, and neurovascular unit disruption in the fetal brain. The data support a placenta–brain axis model in which anti-angiogenic placental signalling, systemic inflammatory mediators, and impaired fetal cerebral perfusion converge to remodel hippocampal architecture during critical developmental windows.