Disrupted brain angiogenesis and blood–brain barrier function underlie cognitive deficits in offspring of preeclampsia‐like pregnancies

Offspring of preeclampsia pregnancies may develop long-term neurovascular and cognitive impairments, but the underlying mechanisms remain unclear. This study examined how prenatal preeclampsia-like conditions alter offspring brain angiogenesis, blood-brain barrier (BBB) integrity and cognition, and sought to identify mechanisms underlying BBB disruption. We also tested whether male and female offspring are differentially affected. Pregnant mice received l-NAME (a nitric oxide inhibitor) from gestational day 7 to 19 to induce a preeclampsia-like syndrome. Offspring were evaluated at postnatal day 5 (P5) and in adulthood (4-5 months). Brain angiogenesis and BBB integrity were assessed by using in vivo and ex vivo imaging, biochemical analyses and endothelial cell assays. Adult cognitive performance was evaluated through a range of behavioural tests. At P5, offspring from l-NAME-treated dams displayed reduced angiogenesis with sex-dependent effects on endothelial tip cells and GLUT1 expression. BBB dysfunction was evidenced by increased permeability and reduced tight-junction proteins (claudin-5, ZO-1), accompanied by elevated cortical HIF-1α and IL-6, with greater impairment in males. Serum from l-NAME offspring, enriched in immunomodulatory cytokines (IL-6, IL-8), induced endothelial activation and barrier disruption in vitro, particularly in males. In adulthood, both male and female offspring exhibited deficits in recognition and spatial memory. Gestational exposure to a preeclampsia-like environment impairs early brain angiogenesis, disrupts BBB integrity via inflammatory and junctional mechanisms, and results in persistent cognitive dysfunction, revealing significant sex-specific vulnerability relevant to long-term neurological risk. KEY POINTS: Children born from pregnancies complicated by preeclampsia may face an increased risk of long-term brain and cognitive problems, but the biological causes have been unclear. Using a mouse model, we show that preeclampsia-like conditions may disrupt early brain blood vessel development and damage the brain's protective barrier. These changes are linked to inflammation and loss of proteins that normally protect brain blood vessels. Male offspring tend to be more severely affected than females, revealing important biological differences in vulnerability. Understanding these mechanisms is critical for developing strategies to protect the brain early in life and reduce the risk of long-term neurological problems in children born to women with preeclampsia.