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

Ashtin B Giambrone,Gene L Bidwell,Junie P Warrington,Omar C Logue,Qingmei Shao

doi:10.3390/ijms20164051

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.

Highlights

Preeclampsia (PE), a hypertensive disorder of pregnancy, is characterized by new onset hypertension with proteinuria, or in the absence of proteinuria, symptoms of other organ damage affecting kidney(s), the liver, or the brain [1]
Placental ischemia in the pregnant female rat induces an increased number of cerebral micro-bleeds, a more pro-inflammatory cerebral-tissue environment, and decreased microglial density in the sub-ventricular zone of fetal brains in utero
We found significant increases in the hematocrits of fetuses exposed to placental ischemia, suggesting systemic hypoxia

Summary

Introduction

Preeclampsia (PE), a hypertensive disorder of pregnancy, is characterized by new onset hypertension with proteinuria, or in the absence of proteinuria, symptoms of other organ damage affecting kidney(s), the liver, or the brain [1]. There is compelling evidence that exposure to PE has lasting effects on the offspring s cognitive abilities. In addition to being the source of the maternal syndrome [9], the dysfunctional placenta fails to meet the metabolic demands of the developing brain [10], resulting in clinical manifestations of neurodevelopmental disorders [11]. Offspring of PE-complicated pregnancies have a 32% increased risk of autism spectrum disorders [12,13,14]. Itionally, whether placental ischemia induces neuroinflammation in the developing brIaninthisisnosttukdnyo,wwne. Induced and modeled placental malperfusion by using the well-established rat model oInf pthlaiscestnutdaly,iswcheeinmdiuac[e2d6]a,nadnmd oddeetelerdmpinlaecdenthtael emffaelcpteorffufisivoendbayyussoinfgistchheewmeilal-oesntafbetliaslhceedrerabtral micmroo-dbelleeodf splaancdenntaeluirsocihneflmaima m[2a6t]i,oann.dWdeetmeremaisnuerdedthteheefnfeucmt obfefrivoef dmaiycsroo-fhiesmchoermrhiaagoensfaestaal cmeraerbkrearl of micmroic-rbole-beldesedasndanvdansceuulraorinfuflnamctimonat,iborna.iWn we mateearscuornetdentht easnuammbeearsoufremoicfrcoe-rheebmraolrerhdaegmeas,aasnadmcyatrokkerine levoeflsmanicdrom-bilcereodgsliaancdhavnagsceusltaor afussnecstsionne,ubrroaiinnflwamatmeractioonnteinnteams barymoenaiscudreayo(fEc1e9r)ebraratlberadienms.a, and cytokine levels and microglia changes to assess neuroinflammation in embryonic day (E19) rat brains Awdnd. itionally, whether placental ischemia induces neuroinflammation in the developing brIaninthisisnosttukdnyo,wwne. induced and modeled placental malperfusion by using the well-established rat model oInf pthlaiscestnutdaly,iswcheeinmdiuac[e2d6]a,nadnmd oddeetelerdmpinlaecdenthtael emffaelcpteorffufisivoendbayyussoinfgistchheewmeilal-oesntafbetliaslhceedrerabtral micmroo-dbelleeodf splaancdenntaeluirsocihneflmaima m[2a6t]i,oann.dWdeetmeremaisnuerdedthteheefnfeucmt obfefrivoef dmaiycsroo-fhiesmchoermrhiaagoensfaestaal cmeraerbkrearl of micmroic-rbole-beldesedasndanvdansceuulraorinfuflnamctimonat,iborna.iWn we mateearscuornetdentht easnuammbeearsoufremoicfrcoe-rheebmraolrerhdaegmeas,aasnadmcyatrokkerine levoeflsmanicdrom-bilcereodgsliaancdhavnagsceusltaor afussnecstsionne,ubrroaiinnflwamatmeractioonnteinnteams barymoenaiscudreayo(fEc1e9r)ebraratlberadienms.a, and cytokine levels and microglia changes to assess neuroinflammation in embryonic day (E19) rat brains

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