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雌性小鼠生殖道的内源性大麻素系统成分在生殖衰老过程中发生变化。

Endocannabinoid System Components of the Female Mouse Reproductive Tract Are Modulated during Reproductive Aging.

机构信息

Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.

Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, SE-14186 Stockholm, Sweden.

出版信息

Int J Mol Sci. 2023 Apr 19;24(8):7542. doi: 10.3390/ijms24087542.

Abstract

The endocannabinoid (eCB) system has gained ground as a key modulator of several female fertility-related processes, under physiological/pathological conditions. Nevertheless, its modulation during reproductive aging remains unclear. This study aimed to investigate the expression levels of the main receptors (cannabinoid receptor 1,CB; cannabinoid receptor 2, CB; G-protein coupled receptor, GPR55; and transient receptor potential vanilloid type 1 channel, TRPV1) and metabolic enzymes (N-acylphosphatidylethanolamine phospholipase D, NAPE-PLD; fatty acid amide hydrolase, FAAH; monoacylglycerol lipase, MAGL; and diacylglycerol lipase, DAGL-α and -β) of this system in the ovaries, oviducts, and uteri of mice at prepubertal, adult, late reproductive, and post-reproductive stages through quantitative ELISA and immunohistochemistry. The ELISA showed that among the receptors, TRPV1 had the highest expression and significantly increased during aging. Among the enzymes, NAPE-PLD, FAAH, and DAGL-β were the most expressed in these organs at all ages, and increased age-dependently. Immunohistochemistry revealed that, regardless of age, NAPE-PLD and FAAH were mainly found in the epithelial cells facing the lumen of the oviduct and uteri. Moreover, in ovaries, NAPE-PLD was predominant in the granulosa cells, while FAAH was sparse in the stromal compartment. Of note, the age-dependent increase in TRPV1 and DAGL-β could be indicative of increased inflammation, while that of NAPE-PLD and FAAH could suggest the need to tightly control the levels of the eCB anandamide at late reproductive age. These findings offer new insights into the role of the eCB system in female reproduction, with potential for therapeutic exploitation.

摘要

内源性大麻素 (eCB) 系统作为多种与女性生育相关过程的关键调节剂,在生理/病理条件下得到了广泛的研究。然而,其在生殖衰老过程中的调节作用尚不清楚。本研究旨在通过定量 ELISA 和免疫组织化学方法,研究该系统的主要受体(大麻素受体 1(CB)、大麻素受体 2(CB2)、G 蛋白偶联受体 55(GPR55)和瞬时受体电位香草酸型 1 通道(TRPV1))和代谢酶(N-酰基磷酸乙醇胺磷脂酶 D(NAPE-PLD)、脂肪酸酰胺水解酶(FAAH)、单酰基甘油脂肪酶(MAGL)和二酰基甘油脂肪酶(DAGL-α 和 -β))在幼年期、成年期、晚期生殖期和生殖后期小鼠卵巢、输卵管和子宫中的表达水平。ELISA 结果显示,在受体中,TRPV1 的表达量最高,且随着年龄的增长显著增加。在酶中,NAPE-PLD、FAAH 和 DAGL-β 在所有年龄段的这些器官中表达最高,并呈年龄依赖性增加。免疫组织化学显示,无论年龄大小,NAPE-PLD 和 FAAH 主要存在于输卵管和子宫腔面向上皮细胞中。此外,在卵巢中,NAPE-PLD 主要存在于颗粒细胞中,而 FAAH 在基质区稀疏存在。值得注意的是,TRPV1 和 DAGL-β 的年龄依赖性增加可能表明炎症增加,而 NAPE-PLD 和 FAAH 的增加可能表明需要在生殖后期严格控制内源性大麻素大麻素的水平。这些发现为内源性大麻素系统在女性生殖中的作用提供了新的见解,并为治疗应用提供了潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a0/10144466/b0397133f9a1/ijms-24-07542-g001.jpg

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