Perinatal Micro-Bleeds and Neuroinflammation in E19 Rat Fetuses Exposed to Utero-Placental Ischemia

Abstract

Offspring of preeclampsia patients have an increased risk of developing neurological deficits and cognitive impairment. While low placental perfusion, common in preeclampsia and growth restriction, has been linked to neurological deficits, a causative link is not fully established. The goal of this study was to test the hypothesis that placental ischemia induces neuroinflammation and micro-hemorrhages in utero. Timed-pregnant Sprague Dawley rats were weight-matched for sham surgery (abdominal incision only) or induced placental ischemia (surgical reduction of utero-placental perfusion (RUPP)); n = 5/group on gestational day 14. Fetal brains (n = 1–2/dam/endpoint) were collected at embryonic day (E19). Placental ischemia resulted in fewer live fetuses, increased fetal demise, increased hematocrit, and no difference in brain water content in exposed fetuses. Additionally, increased cerebral micro-bleeds (identified with H&E staining), pro-inflammatory cytokines: IL-1β, IL-6, and IL-18, eotaxin (CCL11), LIX (CXCL5), and MIP-2 (CXCL2) were observed in RUPP-exposed fetuses. Microglial density in the sub-ventricular zone decreased in RUPP-exposed fetuses, with no change in cortical thickness. Our findings support the hypothesis that exposure to placental ischemia contributes to microvascular dysfunction (increased micro-bleeds), fetal brain inflammation, and reduced microglial density in proliferative brain areas. Future studies will determine whether in utero abnormalities contribute to long-term behavioral deficits in preeclampsia offspring through impaired neurogenesis regulation.

Maternal pre-eclampsia serum increases neurite growth and mitochondrial function through a potential IL-6-dependent mechanism in differentiated SH-SY5Y cells

“…We therefore propose that the elevated IL-6 is responsible, at least partially, for these effects ( Figure 6 ). This may have important implications for our understanding of the physiological relationship between pre-eclampsia and neurodevelopment in vivo , considering IL-6 is able to permeate both the human placenta and the blood-brain barrier ( Zaretsky et al, 2004 ; Banks, 2005 ), and IL-6 is correspondingly elevated in the circulation of human neonates born to pre-eclamptic pregnancies ( Tosun et al, 2010 ) and the brains of rat pups exposed to a pre-clinical model of PE ( Giambrone et al, 2019 ). This suggests IL-6 as a potential pathway for early therapeutic intervention, not to prevent the progression of PE in the mother, but to attenuate its deleterious effects on the fetal brain, although further preclinical and clinical studies will be required to discern this.…”

Supplementation with dietary omega-3 PUFA mitigates fetal brain inflammation and mitochondrial damage caused by high doses of sodium nitrite in maternal rats

“…In preeclampsia and gestational marginal zinc deficiency studies, pregnant rats were sacrificed at E19 [44,45]. In the present study, pregnant rats were treated from E0 to E19, but we did not study the effects of drugs on fetal rats post E19.…”

Brain Vascular Dysfunction in Mothers and Their Children Exposed to Preeclampsia

“…A study demonstrated that the brain of fetuses extracted from RUPP model showed increased levels of proinflammatory cytokines, chemokines, higher incidence of microbleeds, and reduced microglial density in the subventricular zone, either excreted from the fetal brain or originating from maternal blood. 159 In another study, pregnant rats were treated with an inhibitor of nitric oxide synthase, the N-nitro-L-methylarginine, at different gestational ages to induce an early and late-onset preeclampsia-like state. 160 Under the above conditions, the cortical and cerebellar expression of 2 markers of neuroinflammation, was assessed in both mother and pups.…”

“…A study demonstrated that the brain of fetuses extracted from RUPP model showed increased levels of proinflammatory cytokines, chemokines, higher incidence of microbleeds, and reduced microglial density in the subventricular zone, either excreted from the fetal brain or originating from maternal blood. 159…”