Department of Physiology, Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan.
Department of Military Occupational Medicine, Vietnam Military Medical University, Hanoi, Vietnam.
Physiol Genomics. 2023 May 1;55(5):222-234. doi: 10.1152/physiolgenomics.00168.2022. Epub 2023 Mar 20.
We examined the effect of chronic restraint stress and the counteractive effects of daily exercise on the molecular basis of the brain-bone marrow (BM) interactions, by especially focusing on the paraventricular nucleus (PVN) of the hypothalamus. Male Wistar rats were assigned into control, restraint stress, and stress + daily spontaneous exercise (SE) groups. BM and hypothalamic gene expression profiles were examined through the undertaking of RT-PCR and microarrays, respectively. The inflammatory blood cell population was investigated through flow cytometry. Through the use of immunohistochemistry, we examined the presence of BM-derived C-C chemokine receptor type 2 (CCR2)-expressing microglial cells in the rat PVN. The gene expression levels of BM inflammatory factors such as those of interleukin 1 beta and CCR2, and the inflammatory blood cell population were found to be significantly higher in both restrained groups compared with control group. Interestingly, chronic restraint stress alone activated the recruitment of BM-derived CCR2-expressing microglial cells into the PVN, whereas daily spontaneous exercise prevented it. A notable finding was that restraint stress upregulated relative gene expression of hypothalamic matrix metalloproteinase 3 (MMP3), which increases the permeability of the blood-brain barrier (BBB), and that exercise managed to normalize it. Moreover, relative expression of some hypothalamic genes directly involved in the facilitation of cell migration was downregulated by daily exercise. Our findings suggest that daily spontaneous exercise can reduce the numbers of BM-derived CCR2-expressing microglial cells into the PVN through the prevention of stress-induced changes in the hypothalamic gene expression. Chronic restraint stress can upregulate MMP3 gene expression in the rat hypothalamus, whereas daily spontaneous exercise can prevent this stress-induced effect. Stress-induced BM-derived inflammatory cell recruitment into the rat PVN can be prevented by daily spontaneous exercise. Stress-induced increase of hypothalamic MMP3 gene expression may be responsible for BBB injury, thereby allowing for BM-derived inflammatory cells to be recruited and to accumulate in the rat PVN, and to be subsequently involved in the onset of stress-induced hypertension.
我们研究了慢性束缚应激的影响以及每日运动的拮抗作用对脑-骨髓（BM）相互作用的分子基础，特别是重点关注下丘脑室旁核（PVN）。雄性 Wistar 大鼠被分为对照组、束缚应激组和应激+每日自发性运动（SE）组。通过 RT-PCR 和微阵列分别检查 BM 和下丘脑的基因表达谱。通过流式细胞术研究炎症性血细胞群体。通过免疫组织化学，我们检查了 BM 来源的 C-C 趋化因子受体 2（CCR2）表达的小胶质细胞在大鼠 PVN 中的存在。与对照组相比，两组束缚组的 BM 炎症因子（如白细胞介素 1β和 CCR2）的基因表达水平和炎症性血细胞群体均显著升高。有趣的是，慢性束缚应激本身激活了 BM 来源的 CCR2 表达小胶质细胞向 PVN 的募集，而每日自发性运动则阻止了这种募集。一个显著的发现是，束缚应激上调了相对基因表达的下丘脑基质金属蛋白酶 3（MMP3），这增加了血脑屏障（BBB）的通透性，而运动成功地使其正常化。此外，一些直接参与促进细胞迁移的下丘脑基因的相对表达也被每日运动下调。我们的研究结果表明，每日自发性运动可以通过防止应激引起的下丘脑基因表达变化来减少 BM 来源的 CCR2 表达小胶质细胞进入 PVN。慢性束缚应激可以上调大鼠下丘脑 MMP3 基因的表达，而每日自发性运动可以防止这种应激诱导的作用。每日自发性运动可以防止应激诱导的 BM 来源炎症细胞向大鼠 PVN 的募集。应激诱导的下丘脑 MMP3 基因表达增加可能是 BBB 损伤的原因，从而允许 BM 来源的炎症细胞被募集并积累在大鼠 PVN 中，并随后参与应激诱导的高血压的发生。
