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

**Ashtin B. Giambrone 1, Omar C. Logue 2, Qingmei Shao 1, Gene L. Bidwell III 1,2 and Junie P. Warrington 1,\***


Received: 14 July 2019; Accepted: 18 August 2019; Published: 20 August 2019

**Abstract:** O ffspring 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 di fference 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 o ffspring through impaired neurogenesis regulation.

**Keywords:** micro-bleeds; cerebral cytokines; preeclampsia; microglia
