Center for Perinatal Biology, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA.
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697, USA.
Int J Mol Sci. 2021 Jan 12;22(2):680. doi: 10.3390/ijms22020680.
The present study explored the hypothesis that an adverse intrauterine environment caused by maternal undernutrition (MUN) acted through corticosteroid-dependent and -independent mechanisms to program lasting functional changes in the neonatal cerebrovasculature and vulnerability to mild hypoxic-ischemic (HI) injury. From day 10 of gestation until term, MUN and MUN-metyrapone (MUN-MET) group rats consumed a diet restricted to 50% of calories consumed by a pair-fed control; and on gestational day 11 through term, MUN-MET groups received drinking water containing MET (0.5 mg/mL), a corticosteroid synthesis inhibitor. P9/P10 pups underwent unilateral carotid ligation followed 24 h later by 1.5 h exposure to 8% oxygen (HI treatment). An ELISA quantified MUN-, MET-, and HI-induced changes in circulating levels of corticosterone. In P11/P12 pups, MUN programming promoted contractile differentiation in cerebrovascular smooth muscle as determined by confocal microscopy, modulated calcium-dependent contractility as revealed by cerebral artery myography, enhanced vasogenic edema formation as indicated by T2 MRI, and worsened neurobehavior MUN unmasked HI-induced improvements in open-field locomotion and in edema resolution, alterations in calcium-dependent contractility and promotion of contractile differentiation. Overall, MUN imposed multiple interdependent effects on cerebrovascular smooth muscle differentiation, contractility, edema formation, flow-metabolism coupling and neurobehavior through pathways that both required, and were independent of, gestational corticosteroids. In light of growing global patterns of food insecurity, the present study emphasizes that infants born from undernourished mothers may experience greater risk for developing neonatal cerebral edema and sensorimotor impairments possibly through programmed changes in neonatal cerebrovascular function.
母体营养不良（MUN）导致的宫内不良环境通过糖皮质激素依赖和非依赖机制作用，对新生脑血管的功能产生持久的影响，并使其易患轻度缺氧缺血（HI）损伤。从妊娠第 10 天到足月，MUN 和 MUN-美替拉酮（MUN-MET）组大鼠的饮食摄入量限制为对照组的 50%；从妊娠第 11 天到足月，MUN-MET 组大鼠饮用含有 MET（0.5mg/mL）的水，MET 是一种糖皮质激素合成抑制剂。P9/P10 幼鼠行单侧颈总动脉结扎，24 小时后暴露于 8%氧气中 1.5 小时（HI 处理）。ELISA 检测了 MUN、MET 和 HI 诱导的循环皮质酮水平的变化。在 P11/P12 幼鼠中，MUN 编程通过共聚焦显微镜确定促进脑血管平滑肌的收缩分化，通过脑动脉肌描记术揭示调节钙依赖性收缩性，通过 T2 MRI 增强血管源性水肿形成，并使神经行为恶化。MUN 揭示了 HI 诱导的开阔场运动和水肿消退改善、钙依赖性收缩性改变和收缩分化促进作用。总的来说，MUN 通过既需要又独立于妊娠期糖皮质激素的途径，对脑血管平滑肌分化、收缩性、水肿形成、血流代谢耦联和神经行为产生多种相互依赖的影响。鉴于全球日益增长的食物不安全模式，本研究强调，来自营养不良母亲的婴儿可能面临更大的风险，易患新生儿脑水肿和感觉运动障碍，可能是通过新生儿脑血管功能的编程变化。
