低氧对子宫内膜异位症影响的研究进展

doi:10.12280/gjszjk.20200560

摘要/Abstract

摘要：

子宫内膜异位症（EMs）是育龄期女性最常见的妇科疾病之一,是具有恶性行为的良性疾病,可发生于全身各个部位。导致EMs的危险因素众多,主要包括内分泌、遗传、环境和免疫因素。目前EMs的病因仍然未知,近年来有研究表明缺氧是EMs发生的驱动力,缺氧可以通过3个方面影响EMs的发生和发展,一是缺氧过度激活环氧合酶2/前列腺素E₂（COX-2/PGE₂）而上调类固醇激素生成酶,因此促进雌激素生成,同时缺氧降低雌激素受体α（ERα）与ERβ的比值和孕激素受体（PR）,改变类固醇激素的作用效率;二是缺氧激活血管内皮生长因子（VEGF）、血管生成素（Ang）等血管生成因子促进异位病灶快速形成血管,为异位病灶生长提供氧气及营养物质;三是缺氧干扰EMs细胞的正常自噬过程,促进其发生侵袭、转移。综述缺氧参与EMs的发病机制以及相关治疗,以期为临床诊断、治疗提供新视角。

关键词: 子宫内膜异位症, 低氧, 新生血管化,病理性, 雌激素类, 自噬

Abstract:

Endometriosis (EMs) is one of the most common gynecological diseases in women of childbearing age. It is a benign disease with malignant behavior and can occur in various parts of the body. There are many risk factors leading to EMs, including endocrine, genetic, environmental and immune factors. At present, the etiology of EMs is still unknown. Recent studies have shown that hypoxia is the driving force of EMs. Hypoxia can affect the occurrence and development of EMs in three aspects. (1) Hypoxia over-activates COX-2/PGE₂ and up-regulates steroid hormone-producing enzymes, thus promoting estrogen production; at the same time, hypoxia reduces the ratio of ERα to ERβ and PR, and changes the efficiency of steroids. (2) Hypoxia-activated angiogenic factors such as VEGF and Ang promote the rapid formation of blood vessels in ectopic lesions and provide oxygen and nutrients for the growth of ectopic lesions. (3) Hypoxia interferes with the normal autophagy process of EMs cells and promotes its invasion and metastasis. This paper reviews the pathogenesis and related treatment of hypoxia in EMs, in order to provide a new perspective for clinical diagnosis and treatment.

Key words: Endometriosis, Hypoxia, Neovascularization,pathologic, Estrogens, Autophagy

王甜, 郑晶莹, 彭嫄晴, 王楠, 赵淑华. 低氧对子宫内膜异位症影响的研究进展[J]. 国际生殖健康/计划生育, 2021, 40(3): 237-241.

WANG Tian, ZHENG Jing-ying, PENG Yuan-qing, WANG Nan, ZHAO Shu-hua. Research Progress on the Effect of Hypoxia on Endometriosis[J]. Journal of International Reproductive Health/Family Planning, 2021, 40(3): 237-241.

图/表 1

参考文献 32

[1]	Laschke MW, Menger MD. Basic mechanisms of vascularization in endometriosis and their clinical implications[J]. Hum Reprod Update, 2018,24(2):207-224. doi: 10.1093/humupd/dmy001. doi: 10.1093/humupd/dmy001 URL
[2]	Wu MH, Hsiao KY, Tsai SJ. Hypoxia: The force of endometriosis[J]. J Obstet Gynaecol Res, 2019,45(3):532-541. doi: 10.1111/jog.13900. doi: 10.1111/jog.2019.45.issue-3 URL
[3]	Liu H, Zhang Z, Xiong W, et al. Hypoxia-inducible factor-1α promotes endometrial stromal cells migration and invasion by upregulating autophagy in endometriosis[J]. Reproduction, 2017,153(6):809-820. doi: 10.1530/REP-16-0643. doi: 10.1530/REP-16-0643 URL
[4]	Qi QM, Guo SW, Liu XS. Activated Platelets Induce Hypoxia-Inducible Factor-1α Expression Likely through Transforming Growth Factor-β1 in Human Endometrial Stromal Cells[J]. Reprod Dev Med, 2019,3(2):69-76. doi: 10.4103/2096-2924.262390. doi: 10.4103/2096-2924.262390 URL
[5]	Qi Q, Liu X, Zhang Q, et al. Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells[J]. Sci Rep, 2020,10(1):1281. doi: 10.1038/s41598-020-57997-6. doi: 10.1038/s41598-020-57997-6 URL
[6]	Chen PS, Chiu WT, Hsu PL, et al. Pathophysiological implications of hypoxia in human diseases[J]. J Biomed Sci, 2020,27(1):63. doi: 10.1186/s12929-020-00658-7. doi: 10.1186/s12929-020-00658-7 URL
[7]	Lee HC, Lin SC, Wu MH, et al. Induction of Pyruvate Dehydrogenase Kinase 1 by Hypoxia Alters Cellular Metabolism and Inhibits Apoptosis in Endometriotic Stromal Cells[J]. Reprod Sci, 2019,26(6):734-744. doi: 10.1177/1933719118789513. doi: 10.1177/1933719118789513 URL
[8]	Lai ZZ, Yang HL, Ha SY, et al. Cyclooxygenase-2 in Endometriosis[J]. Int J Biol Sci, 2019,15(13):2783-2797. doi: 10.7150/ijbs.35128. doi: 10.7150/ijbs.35128 URL
[9]	Wu MH, Lin SC, Hsiao KY, et al. Hypoxia-inhibited dual-specificity phosphatase-2 expression in endometriotic cells regulates cyclooxygenase-2 expression[J]. J Pathol, 2011,225(3):390-400. doi: 10.1002/path.2963. doi: 10.1002/path.2963 URL
[10]	Lin SC, Li YH, Wu MH, et al. Suppression of COUP-TFII by proinflammatory cytokines contributes to the pathogenesis of endometriosis[J]. J Clin Endocrinol Metab, 2014,99(3):E427-E437. doi: 10.1210/jc.2013-3717. doi: 10.1210/jc.2013-3717 URL
[11]	Fu JL, Hsiao KY, Lee HC, et al. Suppression of COUP-TFII upregulates angiogenin and promotes angiogenesis in endometriosis[J]. Hum Reprod, 2018,33(8):1517-1527. doi: 10.1093/humrep/dey220. doi: 10.1093/humrep/dey220 URL
[12]	Lin SC, Lee HC, Hou PC, et al. Targeting hypoxia-mediated YAP1 nuclear translocation ameliorates pathogenesis of endometriosis without compromising maternal fertility[J]. J Pathol, 2017,242(4):476-487. doi: 10.1002/path.4922. doi: 10.1002/path.2017.242.issue-4 URL
[13]	Arnal JF, Lenfant F, Metivier R, et al. Membrane and Nuclear Estrogen Receptor Alpha Actions: From Tissue Specificity to Medical Implications[J]. Physiol Rev, 2017,97(3):1045-1087. doi: 10.1152/physrev.00024.2016. doi: 10.1152/physrev.00024.2016 URL
[14]	Chantalat E, Valera MC, Vaysse C, et al. Estrogen Receptors and Endometriosis[J]. Int J Mol Sci, 2020,21(8):2815. doi: 10.3390/ijms21082815. doi: 10.3390/ijms21082815 URL
[15]	Wu MH, Lu CW, Chang FM, et al. Estrogen receptor expression affected by hypoxia inducible factor-1α in stromal cells from patients with endometriosis[J]. Taiwan J Obstet Gynecol, 2012,51(1); 50-54. doi: 10.1016/j.tjog.2012.01.010. doi: 10.1016/j.tjog.2012.01.010 URL
[16]	马雪松, 张宗峰. 上皮-间质转化在子宫内膜异位症发病机制中的作用[J]. 国际妇产科学杂志, 2020,47(1):101-105. doi: 10.3969/j.issn.1674-1870.2020.01.024.
[17]	Bulun SE, Monsavais D, Pavone ME, et al. Role of estrogen receptor-β in endometriosis[J]. Semin Reprod Med, 2012,30(1):39-45. doi: 10.1055/s-0031-1299596. doi: 10.1055/s-0031-1299596 URL
[18]	Zhang L, Xiong W, Li N, et al. Estrogen stabilizes hypoxia-inducible factor 1α through G protein-coupled estrogen receptor 1 in eutopic endometrium of endometriosis[J]. Fertil Steril, 2017,107(2):439-447. doi: 10.1016/j.fertnstert.2016.11.008. doi: 10.1016/j.fertnstert.2016.11.008 URL
[19]	Xiong W, Zhang L, Xiong Y, et al. Hypoxia Promotes Invasion of Endometrial Stromal Cells via Hypoxia-Inducible Factor 1α Upregulation-Mediated β-Catenin Activation in Endometriosis[J]. Reprod Sci, 2016,23(4):531-541. doi: 10.1177/1933719115607999. doi: 10.1177/1933719115607999 URL
[20]	高聪, 付兆臣. 缺氧对恶性肿瘤血管生成拟态影响的研究进展[J]. 中国肿瘤外科杂志, 2019,11(5):374-777. doi: 10.3969/j.issn.1674-4136.2019.05.017.
[21]	鲁泽春, 李亚里. 缺氧与子宫内膜异位症的相关性研究进展[J]. 国际妇产科学杂志, 2013,40(1):31-34,46.
[22]	Yildiz C, Kacan T, Akkar OB, et al. Effects of Pazopanib, Sunitinib, and Sorafenib, Anti-VEGF Agents, on the Growth of Experimental Endometriosis in Rats[J]. Reprod Sci, 2015,22(11):1445-1451. doi: 10.1177/1933719115584448. doi: 10.1177/1933719115584448 URL
[23]	Wu MH, Chen KF, Lin SC, et al. Aberrant expression of leptin in human endometriotic stromal cells is induced by elevated levels of hypoxia inducible factor-1alpha[J]. Am J Pathol, 2007,170(2):590-598. doi: 10.2353/ajpath.2007.060477. doi: 10.2353/ajpath.2007.060477 URL
[24]	Hsiao KY, Chang N, Lin SC, et al. Inhibition of dual specificity phosphatase-2 by hypoxia promotes interleukin-8-mediated angiogenesis in endometriosis[J]. Hum Reprod, 2014,29(12):2747-2755. doi: 10.1093/humrep/deu255. doi: 10.1093/humrep/deu255 URL
[25]	Yang S, Wang H, Li D, et al. Role of Endometrial Autophagy in Physiological and Pathophysiological Processes[J]. J Cancer, 2019,10(15):3459-3471. doi: 10.7150/jca.31742. doi: 10.7150/jca.31742 URL
[26]	Liu H, Zhang Z, Xiong W, et al. Long non-coding RNA MALAT1 mediates hypoxia-induced pro-survival autophagy of endometrial stromal cells in endometriosis[J]. J Cell Mol Med, 2019,23(1):439-452. doi: 10.1111/jcmm.13947. doi: 10.1111/jcmm.2019.23.issue-1 URL
[27]	Feng Y, Tan BZ. LncRNA MALAT1 inhibits apoptosis of endometrial stromal cells through miR-126-5p-CREB1 axis by activating PI3K-AKT pathway[J]. Mol Cell Biochem, 2020,475(1/2):185-194. doi: 10.1007/s11010-020-03871-y. doi: 10.1007/s11010-020-03871-y URL
[28]	刘恒炜. 低氧介导自噬在子宫内膜异位症发生发展中的作用及机制研究[D]. 武汉:华中科技大学, 2019.
[29]	Yang S, Wang H, Li D, et al. Role of Endometrial Autophagy in Physiological and Pathophysiological Processes[J]. J Cancer, 2019,10(15):3459-3471. doi: 10.7150/jca.31742. doi: 10.7150/jca.31742 URL
[30]	彭超, 周应芳. 子宫内膜异位症的药物治疗[J]. 山东大学学报(医学版), 2019,57(6):46-50.
[31]	姚书忠, 梁炎春. 重视子宫内膜异位症手术治疗的恰当性和彻底性[J]. 中国实用妇科与产科杂志, 2020,36(1):45-49. doi: 10.19538/j.fk2020010111.
[32]	祝燕莉, 胡晓华, 王冰玉, 等. 内异方抑制信号通路改善子宫内膜异位症大鼠缺氧及炎性微环境[J]. 世界科学技术-中医药现代化, 2020,22(2):385-391. doi: 10.11842/wst.20190121005.