Increased production of inflammatory cytokines and activation of microglia in the fetal brain of preeclamptic mice induced by angiotensin II

• DOI: 10.1016/j.jri.2022.103752
• Publication Date: 2022-09-28T15:40:28Z
• Authors: Yoshihisa Katoh; Takayuki Iriyama; Eriko Yano; Seisuke Sayama; Takahiro Seyama; Hiroko Kotajima-M...; Atsushi Sato; Hiroshi Sakuma; Yoshinobu Iguchi; Midori Yoshikawa; Naoko Inaoka; Mari Ichinose; Masatake Toshimitsu; Kenbun Sone; Keiichi Kumasawa; Takeshi Nagamatsu; Kazutaka Ikeda; Yutaka Osuga
• Keywords: 0303 health sciences; Interleukin-6; Angiotensin II; Brain; 3. Good health; Mice; 03 medical and health sciences; Pre-Eclampsia; Pregnancy; Hypertension; Humans; Animals; Cytokines; Female; Microglia

Preeclampsia (PE) is a hypertensive obstetric disorder with poor prognosis for both the mother and offspring. Infants born to mothers with PE are known to be at increased risk of developing higher brain dysfunction, such as autism. However, how maternal PE can affect the environment in the fetal brain has not been fully elucidated. Here, we examined the impact of PE on the fetal brain in a mouse model of PE induced by angiotensin II (Ang II), focusing on changes in the inflammatory condition. We confirmed that pregnant mice which were continuously administered Ang II exhibited PE phenotypes, including high blood pressure, proteinuria, and fetal growth restriction. Quantitative RT-PCR analysis demonstrated that the brain of fetuses on embryonic day 17.5 (E17.5) in the Ang II-administered pregnant mice showed increased expression of cytokines, interleukin (IL)- 6, IL-17a, tumor necrosis factor-α, interferon-γ, IL-12, IL-4, and IL-10. Immunohistochemical analysis over a wide area, from the tip of the frontal lobe to the posterior cerebral end, on E17.5 revealed that the microglia in the fetal brain of the Ang II-administered group displayed higher solidity and circularity than those of the control group, indicating that the microglia had transformed to an amoeboid morphology and were activated. Our findings suggest that maternal PE may cause altered inflammatory conditions in the fetal brain, which might be associated with the pathological mechanism connecting maternal PE and brain dysfunction in the offspring.