Abstract TP496: Placental Ischemia Exposure Leads to Increased Cerebral Microbleeds in Embryonic Day 19 Rat Offspring

Abstract

Perinatal stroke (cerebrovascular injury) affects more than 1 in 3000 live births and is associated with preeclampsia and low placental perfusion. Previous studies have shown that placental ischemia in the rat, induced by surgical reduction of uterine perfusion pressure (RUPP), leads to increased circulating pro-inflammatory cytokines, similar to preeclampsia patients. While there is a strong link between perinatal stroke and low placental perfusion, it is not known whether pups exposed to placental ischemia develop cerebral microbleeds and neuroinflammation in utero . Thus, this study assessed whether placental ischemia induces microbleeds and a pro-inflammatory environment in brains of embryonic day (E)19 offspring. Sham or RUPP surgery was performed on timed-pregnant Sprague Dawley rats (260g) on gestational day 14, and pup brains extracted on E19. Compared to sham, RUPP-exposed pups had increased number of microbleeds (H&E stain: 2.1±0.4 vs. 0.9±0.2; p=0.007) at E19, indicative of structural microvascular abnormalities in the developing fetal brain. Using a multi-plex cytokine/chemokine kit, E19 rat pups exposed to placental ischemia (n=5 pup brains/group), had higher levels of 7 out of 27 cytokines/chemokines: Eotaxin (5.76±0.26 vs. 3.86±0.84 pg/mg protein; p=0.03), Interleukin (IL)-1β (5.17±0.25 vs. 3.70±0.43 pg/mg; p=0.01), IL-6 (72±10.5 vs. 46.3±7.01 pg/mg; p=0.04), LIX (CXCL5; 45.8±2.2 vs. 30.4±4.7; p=0.01), IL-17 (1.12±0.51 vs. 0.27±0.03; p=0.02), IL-18 (330.1±40.9 vs. 226.5±18.3; p=0.02), and macrophage inflammatory protein 2 (20.8±0.5 vs. 15.7±1.9 pg/mg; p=0.02). The number of microbleeds was positively correlated with cerebral IL-6 levels (p=0.03). Thus, our data support the use of the RUPP model as a tool for assessing underlying mechanisms for perinatal stroke in patients with low placental perfusion or preeclampsia. Future studies will assess the role of IL-6 in mediating increased microbleeds in RUPP offspring.