**1. 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]. Because PE is associated with increased risk of morbidity and mortality for the mother and o ffspring, PE contributes significantly to an increased public health burden. There is compelling evidence that exposure to PE has lasting e ffects on the o ffsprings cognitive abilities. O ffspring of PE patients go on to have lower IQ scores at 3 years of age [2], have impaired working memory [3], and have other neurobehavioral impairments [4,5] that progressively exacerbate cognitive impairment into the geriatric years [6,7]. Even though the underlying pathophysiological mechanisms are not known, placental insu fficiency is believed to play a critical role in these poor neurodevelopmental outcomes [8].

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]. Specifically, o ffspring of PE-complicated pregnancies have a 32% increased risk of autism spectrum disorders [12–14]. Moreover, PE is an independent risk factor for long-term neuropsychiatric morbidity in the o ffspring [15] demonstrating that exposure to maternal factors and/or maternal vascular malperfusion [16] have lasting impacts on learning and memory-function in the o ffspring. The underlying pathophysiological mechanisms are not fully known.

One potential mechanism could be reduced blood flow to the developing placenta and fetus, a finding in some PE-complicated pregnancies. Indeed, studies report increased expression of hyoxia-inducible factor 1 alpha (HIF-1 α) mRNA in placentas from women with preeclampsia [17,18]. The rodent placental ischemia model, induced by surgically reducing utero-placental perfusion pressure (RUPP), is well characterized and shares numerous characteristics with the PE patient. For example, RUPP rats have increased mean arterial blood pressure, with or without proteinuria [19], increased inflammatory cytokines [20,21], and increased anti-angiogenic factors [22,23]. Studies from members of our group have shown that RUPP dams have evidence of cerebrovascular abnormalities [24,25]; however, the impact of placental ischemia on the developing fetal cerebrovasculature has not been investigated. Additionally, whether placental ischemia induces neuroinflammation in the developing brain is not known.

In this study, we induced and modeled placental malperfusion by using the well-established rat model of placental ischemia [26], and determined the e ffect of five days of ischemia on fetal cerebral micro-bleeds and neuroinflammation. We measured the number of micro-hemorrhages as a marker of micro-bleeds and vascular function, brain water content as a measure of cerebral edema, and cytokine levels and microglia changes to assess neuroinflammation in embryonic day (E19) rat brains.
