Cerebrovascular mechanisms of stroke severity in offspring from pre‐eclamptic pregnancy

Offspring from pre-eclamptic pregnancies face elevated ischaemic stroke risk throughout life, yet the mechanisms linking adverse intrauterine exposure to adult cerebrovascular vulnerability remain unknown. Distal leptomeningeal anastomoses (LMAs), which develop during late gestation are key determinants of stroke severity and represent a plausible target of prenatal programming. Here, we show that experimental preeclampsia (ePE) in rats establishes a persistent cerebrovascular structural and transcriptional phenotype in adult offspring. Following transient middle cerebral artery occlusion, ePE-exposed males exhibited increased infarct volume, oedema, enhanced perfusion deficit and smaller LMA diameters relative to normal pregnant offspring, and 83% had microvascular stasis after stroke. Female offspring were protected from stroke-induced brain injury despite sharing a similar transcriptional landscape. RNA sequencing and DNA methylation profiling revealed differentially expressed genes and discrete differentially methylated regions enriched for vascular development and VEGF-Notch signalling in ePE offspring. These findings support the possibility of a developmental origin of cerebrovascular stroke risk, implicating gestational programming of cerebrovascular gene expression as a sex modulated determinant of adult stroke outcome and a potential target for early intervention. KEY POINTS: Offspring born from pre-eclamptic pregnancies have a greater lifetime risk and death from ischaemic stroke, but why this occurs is unknown. Pial collaterals form during the late gestational period and are a key determinant of stroke severity. Using a rat model, we showed that compared to normal pregnancy, male offspring from pre-eclamptic pregnancies had smaller diameter pial collaterals which was associated with decreased collateral recruitment during ischaemic stroke and worsened stroke outcome. RNA analysis revealed altered expression of genes related to blood vessel development and function in adult offspring. These findings suggest that preeclampsia leads to lasting changes in cerebrovascular structure and gene expression which is associated with increased stroke severity in male offspring suggesting a potential window for early intervention.