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Reproductive Biology and Endocrinology
Published in: Reproductive Biology and Endocrinology 1/2022

Open Access 01-12-2022 | Endometriosis | Research

Activation of α7 nicotinic acetylcholine receptor retards the development of endometriosis

Authors: Meihua Hao, Xishi Liu, Sun-Wei Guo

Published in: Reproductive Biology and Endocrinology | Issue 1/2022

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Abstract

Background

Women with endometriosis have been shown to have a reduced vagal tone as compared with controls and vagotomy promoted while vagus nerve stimulation (VNS) decelerated the progression of endometriosis in mice. Extensive research also has shown that the activation of the cholinergic anti-inflammatory pathway by VNS activates α7 nicotinic acetylcholine receptor (α7nAChR), potently reducing inflammation. Yet whether α7nAChR plays any role in endometriosis is unknown. We evaluated its expression in normal endometrium, ovarian and deep endometriotic lesions, and evaluated its role in the development of endometriosis.

Methods

Immunohistochemistry analyses of α7nAChR in endometriotic lesions as well as control endometrium, and quantification of tissue fibrosis by Masson trichrome staining were performed. Mouse experiments were conducted to evaluate the impact of α7nAChR activation or suppression on lesional progression and possible therapeutic effect. Finally, in vitro experiments were conducted to evaluate the effect of activation of α7nAChR on epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT), smooth muscle metaplasia (SMM) and fibrogenesis in an endometriotic epithelial cell line and primary endometriotic stromal cells derived from ovarian endometrioma tissue samples.

Results

Immunostaining of α7nAChR was significantly reduced in human endometriotic epithelial cells as compared with their counterpart in normal endometrium. Lesional α7nAChR staining levels correlated negatively with lesional fibrosis and the severity of dysmenorrhea. The α7nAChR agonist significantly impeded the development of endometriotic lesions in mouse models possibly through hindrance of EMT and FMT. It also demonstrated therapeutic effects in mice with induced deep endometriosis. Treatment of endometriotic epithelial and stromal cells with an α7nAChR agonist significantly abrogated platelet-induced EMT, FMT and SMM, and suppressed cellular contractility and collagen production.

Conclusions

α7nAChR is suppressed in endometriotic lesions, and its activation by pharmacological means can impede EMT, FMT, SMM, and fibrogenesis of endometriotic lesions. As such, α7nAChR can be rightfully viewed as a potential target for therapeutic invention.

Trial registration

Not applicable.
Appendix
Available only for authorised users
Literature
1.
Saunders PTK, Horne AW. Endometriosis: Etiology, pathobiology, and therapeutic prospects. Cell. 2021;184:2807–24.PubMedCrossRef
2.
Barra F, Scala C, Ferrero S. Elagolix sodium for the treatment of women with moderate to severe endometriosis-associated pain. Drugs Today (Barc). 2019;55:237–46.CrossRef
3.
Vercellini P, Vigano P, Barbara G, Buggio L, Somigliana E, Luigi Mangiagalli' Endometriosis Study G. Elagolix for endometriosis: all that glitters is not gold. Hum Reprod. 2019;34:193–9.
4.
Burla L, Kalaitzopoulos DR, Metzler JM, Scheiner D, Imesch P. Popularity of endocrine endometriosis drugs and limited alternatives in the present and foreseeable future: A survey among 1420 affected women. Eur J Obstet Gynecol Reprod Biol. 2021;262:232–8.PubMedCrossRef
5.
Garcia-Velasco JA, Somigliana E. Management of endometriomas in women requiring IVF: to touch or not to touch. Hum Reprod. 2009;24:496–501.PubMedCrossRef
6.
de Ziegler D, Borghese B, Chapron C. Endometriosis and infertility: pathophysiology and management. Lancet. 2010;376:730–8.PubMedCrossRef
7.
Coccia ME, Rizzello F, Mariani G, Bulletti C, Palagiano A, Scarselli G. Ovarian surgery for bilateral endometriomas influences age at menopause. Hum Reprod. 2011;26:3000–7.PubMedCrossRef
8.
Vercellini P, Vigano P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10:261–75.PubMedCrossRef
9.
Gonzalez-Ramos R, Van Langendonckt A, Defrere S, Lousse JC, Colette S, Devoto L, et al. Involvement of the nuclear factor-kappaB pathway in the pathogenesis of endometriosis. Fertil Steril. 2010;94:1985–94.PubMedCrossRef
10.
Guo SW. Nuclear factor-kappab (NF-kappaB): an unsuspected major culprit in the pathogenesis of endometriosis that is still at large? Gynecol Obstet Invest. 2007;63:71–97.PubMedCrossRef
11.
Riccio L, Santulli P, Marcellin L, Abrao MS, Batteux F, Chapron C. Immunology of endometriosis. Best Pract Res Clin Obstet Gynaecol. 2018;50:39–49.PubMedCrossRef
12.
Koninckx PR, Craessaerts M, Timmerman D, Cornillie F, Kennedy S. Anti-TNF-alpha treatment for deep endometriosis-associated pain: a randomized placebo-controlled trial. Hum Reprod. 2008;23:2017–23.PubMedPubMedCentralCrossRef
13.
Guo SW, Groothuis PG. Is it time for a paradigm shift in drug research and development in endometriosis/adenomyosis? Hum Reprod Update. 2018;24:577–98.PubMedCrossRef
14.
Grammatis AL, Georgiou EX, Becker CM. Pentoxifylline for the treatment of endometriosis-associated pain and infertility. Cochrane Database Syst Rev. 2021;8:CD007677.PubMed
15.
Berthoud HR, Neuhuber WL. Functional and chemical anatomy of the afferent vagal system. Auton Neurosci. 2000;85:1–17.PubMedCrossRef
16.
17.
Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458–62.PubMedCrossRef
18.
19.
20.
Maier SF, Goehler LE, Fleshner M, Watkins LR. The role of the vagus nerve in cytokine-to-brain communication. Ann N Y Acad Sci. 1998;840:289–300.PubMedCrossRef
21.
Kessler W, Diedrich S, Menges P, Ebker T, Nielson M, Partecke LI, et al. The role of the vagus nerve: modulation of the inflammatory reaction in murine polymicrobial sepsis. Mediators Inflamm. 2012;2012: 467620.PubMedPubMedCentralCrossRef
22.
Johnson RL, Murray ST, Camacho DK, Wilson CG. Vagal nerve stimulation attenuates IL-6 and TNFalpha expression in respiratory regions of the developing rat brainstem. Respir Physiol Neurobiol. 2016;229:1–4.PubMedCrossRef
23.
Koopman FA, Chavan SS, Miljko S, Grazio S, Sokolovic S, Schuurman PR, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2016;113:8284–9.PubMedPubMedCentralCrossRef
24.
Zhao M, He X, Bi XY, Yu XJ, Gil Wier W, Zang WJ. Vagal stimulation triggers peripheral vascular protection through the cholinergic anti-inflammatory pathway in a rat model of myocardial ischemia/reperfusion. Basic Res Cardiol. 2013;108:345.PubMedCrossRef
25.
Zhang L, Lu J, Wu Z. Auricular Vagus Nerve Stimulation Attenuates Lipopolysaccharide Induced Acute Lung Injury by Inhibiting Neutrophil Infiltration and Neutrophil Extracellular Traps Formation. Shock. 2021.
26.
Hao M, Liu X, Rong P, Li S, Guo SW. Reduced vagal tone in women with endometriosis and auricular vagus nerve stimulation as a potential therapeutic approach. Sci Rep. 2021;11:1345.PubMedPubMedCentralCrossRef
27.
He X, Zhao M, Bi X, Sun L, Yu X, Zhao M, et al. Novel strategies and underlying protective mechanisms of modulation of vagal activity in cardiovascular diseases. Br J Pharmacol. 2015;172:5489–500.PubMedPubMedCentralCrossRef
28.
29.
Yamada-Nomoto K, Yoshino O, Akiyama I, Ushijima A, Ono Y, Shima T, et al. Alpha-7 nicotinic acetylcholine receptor (nAChR) agonist inhibits the development of endometriosis by regulating inflammation. Am J Reprod Immunol. 2016;76:491–8.PubMedCrossRef
30.
31.
Zhang Q, Duan J, Liu X, Guo SW. Platelets drive smooth muscle metaplasia and fibrogenesis in endometriosis through epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation. Mol Cell Endocrinol. 2016;428:1–16.PubMedCrossRef
32.
Zhang Q, Duan J, Olson M, Fazleabas A, Guo SW. Cellular Changes Consistent With Epithelial-Mesenchymal Transition and Fibroblast-to-Myofibroblast Transdifferentiation in the Progression of Experimental Endometriosis in Baboons. Reprod Sci. 2016;23:1409–21.PubMedPubMedCentralCrossRef
33.
Yan D, Liu X, Guo SW. Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis. Sci Rep. 2019;9:2698.PubMedPubMedCentralCrossRef
34.
Council NR. Guide for the Care and Use of Laboratory Animals: Washington. D.C: National Academies Press; 1996.
35.
Ding D, Cai X, Zheng H, Guo SW, Liu X. Scutellarin Suppresses Platelet Aggregation and Stalls Lesional Progression in Mouse With Induced Endometriosis. Reprod Sci. 2019;26:1417–28.PubMedCrossRef
36.
Donnez O, Van Langendonckt A, Defrere S, Colette S, Van Kerk O, Dehoux JP, et al. Induction of endometriotic nodules in an experimental baboon model mimicking human deep nodular lesions. Fertil Steril. 2013;99(783–9): e3.
37.
Dorning A, Dhami P, Panir K, Hogg C, Park E, Ferguson GD, et al. Bioluminescent imaging in induced mouse models of endometriosis reveals differences in four model variations. Dis Model Mech. 2021;14.
38.
Silva RC, Terra FF, Guise YF, Prado MA, Prado VF, Hiyane MI, et al. Reduced expression of VAChT increases renal fibrosis. Pathophysiology. 2016;23:229–36.PubMedCrossRef
39.
Leite PE, Gandia L, de Pascual R, Nanclares C, Colmena I, Santos WC, et al. Selective activation of alpha7 nicotinic acetylcholine receptor (nAChRalpha7) inhibits muscular degeneration in mdx dystrophic mice. Brain Res. 2014;1573:27–36.PubMedCrossRef
40.
Yan D, Liu X, Guo SW. The establishment of a mouse model of deep endometriosis. Hum Reprod. 2019;34:235–47.PubMedCrossRef
41.
Somigliana E, Vigano P, Rossi G, Carinelli S, Vignali M, Panina-Bordignon P. Endometrial ability to implant in ectopic sites can be prevented by interleukin-12 in a murine model of endometriosis. Hum Reprod. 1999;14:2944–50.PubMedCrossRef
42.
Lu Y, Nie J, Liu X, Zheng Y, Guo SW. Trichostatin A, a histone deacetylase inhibitor, reduces lesion growth and hyperalgesia in experimentally induced endometriosis in mice. Hum Reprod. 2010;25:1014–25.PubMedCrossRef
43.
Long Q, Liu X, Guo SW. Surgery accelerates the development of endometriosis in mice. Am J Obstet Gynecol. 2016;215(320):e1–15.
44.
Long Q, Zheng H, Liu X, Guo SW. Perioperative Intervention by beta-Blockade and NF-kappaB Suppression Reduces the Recurrence Risk of Endometriosis in Mice Due to Incomplete Excision. Reprod Sci. 2019;26:697–708.PubMedCrossRef
45.
Huang Q, Liu X, Guo S-W. Changing prostaglandin E2 (PGE2) signaling during lesional progression and exacerbation of endometriosis by inhibition of PGE2 receptor EP2 and EP4 Reprod Med Biol. 2021. In press.
46.
Zeitvogel A, Baumann R, Starzinski-Powitz A. Identification of an invasive, N-cadherin-expressing epithelial cell type in endometriosis using a new cell culture model. Am J Pathol. 2001;159:1839–52.PubMedPubMedCentralCrossRef
47.
Zhang Q, Ding D, Liu X, Guo SW. Activated Platelets Induce Estrogen Receptor beta Expression in Endometriotic Stromal Cells. Gynecol Obstet Invest. 2015;80:187–92.PubMedCrossRef
48.
Yan D, Liu X, Xu H, Guo SW. Platelets induce endothelial-mesenchymal transition and subsequent fibrogenesis in endometriosis. Reprod Biomed Online. 2020;41:500–17.PubMedCrossRef
49.
Team RDC. R: A Language and Environment for Statistical Computing. In. Vienna, Austria: R Foundation for Statistical Computing; 2016.
50.
Liu X, Zhang Q, Guo SW. Histological and Immunohistochemical Characterization of the Similarity and Difference Between Ovarian Endometriomas and Deep Infiltrating Endometriosis. Reprod Sci. 2018;25:329–40.PubMedCrossRef
51.
Baron JA. Beneficial effects of nicotine and cigarette smoking: the real, the possible and the spurious. Br Med Bull. 1996;52:58–73.PubMedCrossRef
52.
Parazzini F, Vercellini P, Panazza S, Chatenoud L, Oldani S, Crosignani PG. Risk factors for adenomyosis. Hum Reprod. 1997;12:1275–9.PubMedCrossRef
53.
Hu S, Wang Y, Li H. The Regulation Effect of alpha7nAChRs and M1AChRs on Inflammation and Immunity in Sepsis. Mediators Inflamm. 2021;2021:9059601.PubMedPubMedCentral
54.
Lagana AS, La Rosa VL, Rapisarda AMC, Valenti G, Sapia F, Chiofalo B, et al. Anxiety and depression in patients with endometriosis: impact and management challenges. Int J Womens Health. 2017;9:323–30.PubMedPubMedCentralCrossRef
55.
Della Corte L, Di Filippo C, Gabrielli O, Reppuccia S, La Rosa VL, Ragusa R, et al. The Burden of Endometriosis on Women's Lifespan: A Narrative Overview on Quality of Life and Psychosocial Wellbeing. Int J Environ Res Public Health. 2020;17.
56.
Casalechi M, Vieira-Lopes M, Quessada MP, Arao TC, Reis FM. Endometriosis and related pelvic pain: association with stress, anxiety and depressive symptoms. Minerva Obstet Gynecol. 2021;73:283–9.PubMedCrossRef
57.
Facchin F, Buggio L, Roncella E, Somigliana E, Ottolini F, Dridi D, et al. Sleep disturbances, fatigue and psychological health in women with endometriosis: a matched pair case-control study. Reprod Biomed Online. 2021;43:1027–34.PubMedCrossRef
58.
Guo SW, Zhang Q, Liu X. Social psychogenic stress promotes the development of endometriosis in mouse. Reprod Biomed Online. 2017;34:225–39.PubMedCrossRef
59.
Long Q, Liu X, Qi Q, Guo SW. Chronic stress accelerates the development of endometriosis in mouse through adrenergic receptor beta2. Hum Reprod. 2016;31:2506–19.PubMedCrossRef
60.
Ding D, Wang X, Chen Y, Benagiano G, Liu X, Guo S-W. Evidence in support for the progressive nature of ovarian endometriomas. J Clin Endocrinol Metab. 2020. In press.
61.
Gorman JM, Sloan RP. Heart rate variability in depressive and anxiety disorders. Am Heart J. 2000;140:77–83.PubMedCrossRef
62.
Goodnick PJ, Rush AJ, George MS, Marangell LB, Sackeim HA. Vagus nerve stimulation in depression. Expert Opin Pharmacother. 2001;2:1061–3.PubMedCrossRef
63.
George MS, Nahas Z, Borckardt JJ, Anderson B, Burns C, Kose S, et al. Vagus nerve stimulation for the treatment of depression and other neuropsychiatric disorders. Expert Rev Neurother. 2007;7:63–74.PubMedCrossRef
64.
Miu AC, Heilman RM, Miclea M. Reduced heart rate variability and vagal tone in anxiety: trait versus state, and the effects of autogenic training. Auton Neurosci. 2009;145:99–103.PubMedCrossRef
65.
Zhang S, He JK, Meng H, Zhao B, Zhao YN, Wang Y, et al. Effects of transcutaneous auricular vagus nerve stimulation on brain functional connectivity of medial prefrontal cortex in patients with primary insomnia. Anat Rec (Hoboken). 2021;304:2426–35.CrossRef
66.
Nisolle M, Donnez J. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril. 1997;68:585–96.PubMedCrossRef
67.
Yang YH, Fang HL, Zhao M, Wei XL, Zhang N, Wang S, et al. Specific alpha7 nicotinic acetylcholine receptor agonist ameliorates isoproterenol-induced cardiac remodelling in mice through TGF-beta1/Smad3 pathway. Clin Exp Pharmacol Physiol. 2017;44:1192–200.PubMedCrossRef
68.
Urata Y, Osuga Y, Izumi G, Takamura M, Koga K, Nagai M, et al. Interleukin-1beta stimulates the secretion of thymic stromal lymphopoietin (TSLP) from endometrioma stromal cells: possible involvement of TSLP in endometriosis. Hum Reprod. 2012;27:3028–35.PubMedCrossRef
69.
Chang KK, Liu LB, Li H, Mei J, Shao J, Xie F, et al. TSLP induced by estrogen stimulates secretion of MCP-1 and IL-8 and growth of human endometrial stromal cells through JNK and NF-kappaB signal pathways. Int J Clin Exp Pathol. 2014;7:1889–99.PubMedPubMedCentral
70.
Xiao F, Liu X, Guo SW. Platelets and Regulatory T Cells May Induce a Type 2 Immunity That Is Conducive to the Progression and Fibrogenesis of Endometriosis. Front Immunol. 2020;11: 610963.PubMedPubMedCentralCrossRef
71.
Dong J, Segawa R, Mizuno N, Hiratsuka M, Hirasawa N. Inhibitory effects of nicotine derived from cigarette smoke on thymic stromal lymphopoietin production in epidermal keratinocytes. Cell Immunol. 2016;302:19–25.PubMedCrossRef
Metadata
Title
Activation of α7 nicotinic acetylcholine receptor retards the development of endometriosis
Authors
Meihua Hao
Xishi Liu
Sun-Wei Guo
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Reproductive Biology and Endocrinology / Issue 1/2022
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/s12958-022-00955-w

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