Mild intrauterine hypoperfusion reproduces neurodevelopmental disorders observed in prematurity OPEN

International audienceSevere intrauterine ischemia is detrimental to the developing brain. The impact of mild intrauterine hypoperfusion on neurological development, however, is still unclear. We induced mild intrauterine hypoperfusion in rats on embryonic day 17 via arterial stenosis with metal microcoils wrapped around the uterine and ovarian arteries. All pups were born with significantly decreased birth weights. Decreased gray and white matter areas were observed without obvious tissue damage. Pups presented delayed newborn reflexes, muscle weakness, and altered spontaneous activity. The levels of proteins indicative of inflammation and stress in the vasculature, i.e., RANTES, vWF, VEGF, and adiponectin, were upregulated in the placenta. The levels of mRNA for proteins associated with axon and astrocyte development were downregulated in fetal brains. The present study demonstrates that even mild intrauterine hypoperfusion can alter neurological development, which mimics the clinical signs and symptoms of children with neurodevelopmental disorders born prematurely or with intrauterine growth restriction. In the past three decades, the incidence of mild brain injuries associated with prematurity, i.e., preterm birth (born at < 37 weeks of gestation) and low birth weight (LBW, < 2500 g), and intrauterine growth restriction (IUGR, birth weight < 10 th percentile for gestational age) has been increasing 1–3. Mild brain injuries include decreased white matter volume and cortical thickness with no obvious periventricular leukomalacia (PVL) or focal lesions. Infants with mild brain injuries frequently present with mild neurodevelopmental disorders (NDDs), such as attention-deficit/hyperactivity disorder (ADHD) and borderline intellectual functioning 4. Mild NDDs associated with prematurity and IUGR have been increasing, and this phenomenon is now recognized as a critical social issue in developed countries; approximately 20% of very LBW (< 1500 g) infants and 50% of extremely LBW (< 1000 g) infants exhibit mild NDDs 5–7. In contrast, the incidence of severe brain injuries associated with prematurity and IUGR, such as cystic PVL, has been decreasing because of improved medical care 1–3. Similarly, the incidence of severe neurological sequelae associated with prematurity and IUGR, such as cerebral palsy, have also been decreasing 8. The etiology of preterm birth, LBW, and IUGR is multifactorial, and the identifiable causes of these three conditions largely overlap. Placental hypoperfusion and intrauterine infection/inflammation are considered the two major causes 9. In many cases in clinical practice, the etiology is difficult to identify and may be a combination of several causes. Thus, the impact of intrauterine hypoperfusion alone, especially mild hypoperfusion, on brain development is still unclear. The influence of severe intrauterine ischemia on the immature brain has been thoroughly explored, as most animal studies on intrauterine ischemia have been performed using models that involve the complete blockade of the blood supply to the uterus or fetus. In contrast, the influence of mild intrauterine hypoperfusion (MIUH) on the immature brain has barely been explored as there is no established model for MIUH. We previously used a model involving a suture ligation of an ovarian artery 10. To better replicate clinically relevant prenatal hypoper-fusion, in the present study, we mildly reduced blood flow to the uteri of pregnant rats via stenosis of the ovaria