Tetramethylpyrazine Stalls Lesional Progression via Inducing Senescence in Mouse with Induced Deep Endometriosis

Main Article Content

Min Luo, M.D. Xianjun Cai, M.D. Xishi Liu, M.D., Ph.D. Dingmin Yan Sun-Wei Guo, M.D., Ph.D.


So far, the pressing need for the development of non-hormonal therapeutics for endometriosis has been unfulfilled. In light of the evidence that platelets play important roles in the development of endometriosis and that tetramethylpyrazine has therapeutic potential, we tested the hypothesis that tetramethylpyrazine can induce cellular senescence in endometriotic lesions, hindering fibrogenesis in mice with induced deep endometriosis and that the combined use of tetramethylpyrazine and sodium tanshinone IIA sulfonate may have a synergistic effect. We induced deep endometriosis in 32 female Balb/C mice, and then randomly divided mice into equal-sized four groups: low- and high-dose tetramethylpyrazine, low-dose tetramethylpyrazine plus low-dose tanshinone IIA sulfonate and inert vehicle control. After two weeks of treatment, their lesion tissues were removed and procured. All lesions were weighed, and lesion fibrosis was quantitated by Masson trichrome staining. In addition, cellular senescence in lesions was evaluated by senescence-associated β-galactosidase, along with immunohistochemistry analyses of p53, Salvador 1, cellular communication network factor 1, hyaluronan synthase 2, surviving and granulocyte-macrophage colony stimulating factor and other markers. We found that tetramethylpyrazine treatment significantly decreased lesion weight, arrested lesional progression and ameliorated pain behaviour ostensibly via inducing senescence by p53 activation, and induction of Salvador 1 and cellular communication network factor 1 while suppressing hyaluronan synthase 2, survivin and granulocyte-macrophage colony stimulating factor, resulting in increased apoptosis and reduced lesional infiltration of alternatively activated macrophages. Tetramethylpyrazine treatment also significantly reduced the plasma concentration of P-selectin and hyaluronic acid, possibly leading to reduced lesional platelet aggregation. Thus, we conclude that tetramethylpyrazine holds the promise as therapeutics for treating endometriosis, but the tetramethylpyrazine plus tanshinone IIA sulfonate did not further enhance the therapeutic effect. These results further underscore the notion that induced senescence may play an antifibrotic role in endometriosis, and activating the senescence pathway, through treatment with tetramethylpyrazine or other similar drugs, may be a novel avenue for treating endometriosis.

Keywords: Endometriosis, mouse, platelet, senescence, tanshinone IIA, tetramethylpyrazine

Article Details

How to Cite
LUO, Min et al. Tetramethylpyrazine Stalls Lesional Progression via Inducing Senescence in Mouse with Induced Deep Endometriosis. Medical Research Archives, [S.l.], v. 10, n. 11, nov. 2022. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/3341>. Date accessed: 17 june 2024. doi: https://doi.org/10.18103/mra.v10i11.3341.
Research Articles


1. Giudice LC, Kao LC. Endometriosis. Lancet. Nov 13-19 2004;364(9447):1789-99. doi:S0140673604174035 [pii]
2. 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. Jul 2021;262:232-238. doi:10.1016/j.ejogrb.2021.05.040
3. Vercellini P, Crosignani P, Somigliana E, Vigano P, Frattaruolo MP, Fedele L. 'Waiting for Godot': a commonsense approach to the medical treatment of endometriosis. Hum Reprod. Jan 2011;26(1):3-13. doi:deq302 [pii]
4. Guo SW, Groothuis PG. Is it time for a paradigm shift in drug research and development in endometriosis/adenomyosis? Hum Reprod Update. Sep 1 2018;24(5):577-598. doi:10.1093/humupd/dmy020
5. Hadfield R, Mardon H, Barlow D, Kennedy S. Delay in the diagnosis of endometriosis: a survey of women from the USA and the UK. Hum Reprod. Apr 1996;11(4):878-80.
6. Liu X, Zhang Q, Guo SW. Histological and Immunohistochemical Characterization of the Similarity and Difference Between Ovarian Endometriomas and Deep Infiltrating Endometriosis. Reprod Sci. Mar 2018;25(3):329-340. doi:10.1177/1933719117718275
7. Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. Jul 6 2012;18(7):1028-40. doi:10.1038/nm.2807
8. 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.
9. Jun JI, Lau LF. Resolution of organ fibrosis. J Clin Invest. Jan 2 2018;128(1):97-107. doi:10.1172/JCI93563
10. Krizhanovsky V, Yon M, Dickins RA, et al. Senescence of activated stellate cells limits liver fibrosis. Cell. Aug 22 2008;134(4):657-67. doi:10.1016/j.cell.2008.06.049
11. Jun JI, Lau LF. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat Cell Biol. Jul 2010;12(7):676-85. doi:10.1038/ncb2070
12. Yan D, Liu X, Guo SW. The establishment of a mouse model of deep endometriosis. Hum Reprod. Feb 1 2019;34(2):235-247. doi:10.1093/humrep/dey361
13. Luo M, Cai X, Yan D, Liu X, Guo SW. Sodium tanshinone IIA sulfonate restrains fibrogenesis through induction of senescence in mice with induced deep endometriosis. Reprod Biomed Online. May 3 2020;doi:10.1016/j.rbmo.2020.04.006
14. Huang S, Xiao F, Guo SW, Zhang T. Tetramethylpyrazine Retards the Progression and Fibrogenesis of Endometriosis. Reprod Sci. Apr 2022;29(4):1170-1187. doi:10.1007/s43032-021-00813-x
15. Yang Y, Wang X, Chen G, Deng L, Xu X. [Research of therapeutical effect and immunologic mechanism of Jiawei Foshou San on model rats of endometriosis]. Zhongguo Zhong Yao Za Zhi. Nov 2011;36(21):3001-6.
16. Tan Y, Zhang C, Zhang Y, et al. Combination of ferulic acid, ligustrazine and tetrahydropalmatine inhibits invasion and metastasis through MMP/TIMP signaling in endometriosis. PeerJ. 2021;9:e11664. doi:10.7717/peerj.11664
17. Zhang C, Zhang Y, Pan H, et al. Combination of Ferulic Acid, Ligustrazine and Tetrahydropalmatine attenuates Epithelial-mesenchymal Transformation via Wnt/beta-catenin Pathway in Endometriosis. Int J Biol Sci. 2021;17(10):2449-2460. doi:10.7150/ijbs.60167
18. Sheu JR, Kan YC, Hung WC, Ko WC, Yen MH. Mechanisms involved in the antiplatelet activity of tetramethylpyrazine in human platelets. Thromb Res. Nov 1 1997;88(3):259-70. doi:10.1016/s0049-3848(97)00253-3
19. Ji NF, Xie YC, Zhang MS, et al. Ligustrazine corrects Th1/Th2 and Treg/Th17 imbalance in a mouse asthma model. Int Immunopharmacol. Jul 2014;21(1):76-81. doi:10.1016/j.intimp.2014.04.015
20. Kao TK, Chang CY, Ou YC, et al. Tetramethylpyrazine reduces cellular inflammatory response following permanent focal cerebral ischemia in rats. Exp Neurol. Sep 2013;247:188-201. doi:10.1016/j.expneurol.2013.04.010
21. Guo L, Wang A, Sun Y, Xu C. Evaluation of antioxidant and immunity function of tetramethylpyrazine phosphate tablets in vivo. Molecules. May 8 2012;17(5):5412-21. doi:10.3390/molecules17055412
22. Wu X, Zhang F, Xiong X, et al. Tetramethylpyrazine reduces inflammation in liver fibrosis and inhibits inflammatory cytokine expression in hepatic stellate cells by modulating NLRP3 inflammasome pathway. IUBMB life. Apr 2015;67(4):312-21. doi:10.1002/iub.1348
23. Cai X, Chen Z, Pan X, et al. Inhibition of angiogenesis, fibrosis and thrombosis by tetramethylpyrazine: mechanisms contributing to the SDF-1/CXCR4 axis. PLoS One. 2014;9(2):e88176. doi:10.1371/journal.pone.0088176
24. Zhao S, Zhang Z, Yao Z, et al. Tetramethylpyrazine attenuates sinusoidal angiogenesis via inhibition of hedgehog signaling in liver fibrosis. IUBMB life. Feb 2017;69(2):115-127. doi:10.1002/iub.1598
25. Tang Q, Shang F, Wang X, et al. Combination use of ferulic acid, ligustrazine and tetrahydropalmatine inhibits the growth of ectopic endometrial tissue: a multi-target therapy for endometriosis rats. J Ethnopharmacol. Feb 12 2014;151(3):1218-1225.
doi:S0378-8741(13)00929-X [pii]
26. Chen Y, Wei J, Zhang Y, et al. Anti-endometriosis Mechanism of Jiawei Foshou San Based on Network Pharmacology. Front Pharmacol. 2018;9:811. doi:10.3389/fphar.2018.00811
27. Wei J, Zhao B, Zhang C, et al. Jiawei Foshou San Induces Apoptosis in Ectopic Endometrium Based on Systems Pharmacology, Molecular Docking, and Experimental Evidence. Evid Based Complement Alternat Med. 2019;2019:2360367. doi:10.1155/2019/2360367
28. He L, He X, Lowe SW, Hannon GJ. microRNAs join the p53 network--another piece in the tumour-suppression puzzle. Nature reviews Cancer. Nov 2007;7(11):819-22. doi:10.1038/nrc2232
29. Borkham-Kamphorst E, Schaffrath C, Van de Leur E, et al. The anti-fibrotic effects of CCN1/CYR61 in primary portal myofibroblasts are mediated through induction of reactive oxygen species resulting in cellular senescence, apoptosis and attenuated TGF-beta signaling. Biochim Biophys Acta. May 2014;1843(5):902-14. doi:10.1016/j.bbamcr.2014.01.023
30. Kim KH, Chen CC, Monzon RI, Lau LF. Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Molecular and cellular biology. May 2013;33(10):2078-90. doi:10.1128/MCB.00049-13
31. Seo E, Kim WY, Hur J, et al. The Hippo-Salvador signaling pathway regulates renal tubulointerstitial fibrosis. Sci Rep. Aug 23 2016;6:31931. doi:10.1038/srep31931
32. Li Y, Liang J, Yang T, et al. Hyaluronan synthase 2 regulates fibroblast senescence in pulmonary fibrosis. Matrix biology : journal of the International Society for Matrix Biology. Sep 2016;55:35-48. doi:10.1016/j.matbio.2016.03.004
33. Han L, Bian H, Ouyang J, Bi Y, Yang L, Ye S. Wenyang Huazhuo Tongluo formula, a Chinese herbal decoction, improves skin fibrosis by promoting apoptosis and inhibiting proliferation through down-regulation of survivin and cyclin D1 in systemic sclerosis. BMC Complement Altern Med. Feb 20 2016;16:69. doi:10.1186/s12906-016-1056-6
34. Duan J, Liu X, Guo S-W. The M2a macrophage subset may be critically involved in fibrogenesis of endometriosis in mouse. Reprod Biomed Online. 2018;37(3):254-268. doi:10.1016/j.rbmo.2018.05.017.
35. Sun YY, Li XF, Meng XM, Huang C, Zhang L, Li J. Macrophage Phenotype in Liver Injury and Repair. Scand J Immunol. Mar 2017;85(3):166-174. doi:10.1111/sji.12468
36. Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging cell. Aug 2015;14(4):644-58. doi:10.1111/acel.12344
37. Donnez O, Van Langendonckt A, Defrere S, et al. Induction of endometriotic nodules in an experimental baboon model mimicking human deep nodular lesions. Fertil Steril. Mar 1 2013;99(3):783-789 e3. doi:S0015-0282(12)02344-8 [pii]
38. Animals. NRCUCftUotGftCaUoL. Guide for the Care and Use of Laboratory Animals. National Academies Press 2011.
39. Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. Mar 2008;22(3):659-61. doi:10.1096/fj.07-9574LSF
40. Wei Y, Liu J, Zhang H, et al. Ligustrazine attenuates inflammation and the associated chemokines and receptors in ovalbumine-induced mouse asthma model. Environ Toxicol Pharmacol. Sep 2016;46:55-61. doi:10.1016/j.etap.2016.07.005
41. Meng D, Lu H, Huang S, et al. Comparative pharmacokinetics of tetramethylpyrazine phosphate in rat plasma and extracellular fluid of brain after intranasal, intragastric and intravenous administration. Acta Pharm Sin B. Feb 2014;4(1):74-8. doi:10.1016/j.apsb.2013.12.009
42. 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. Dec 1999;14(12):2944-50.
43. Henderson J, Terenghi G, McGrouther DA, Ferguson MW. The reinnervation pattern of wounds and scars may explain their sensory symptoms. J Plast Reconstr Aesthet Surg. 2006;59(9):942-50. doi:10.1016/j.bjps.2005.11.038
44. Ozturk N, Erin N, Tuzuner S. Changes in tissue substance P levels in patients with carpal tunnel syndrome. Neurosurgery. Dec 2010;67(6):1655-60; discussion 1660-1. doi:10.1227/NEU.0b013e3181fa7032
45. Fisher PW, Zhao Y, Rico MC, et al. Increased CCN2, substance P and tissue fibrosis are associated with sensorimotor declines in a rat model of repetitive overuse injury. J Cell Commun Signal. Mar 2015;9(1):37-54. doi:10.1007/s12079-015-0263-0
46. Leal EC, Carvalho E, Tellechea A, et al. Substance P promotes wound healing in diabetes by modulating inflammation and macrophage phenotype. The American journal of pathology. Jun 2015;185(6):1638-48. doi:10.1016/j.ajpath.2015.02.011
47. Kant V, Kumar D, Kumar D, et al. Topical application of substance P promotes wound healing in streptozotocin-induced diabetic rats. Cytokine. May 2015;73(1):144-55. doi:10.1016/j.cyto.2014.12.015
48. Yang L, Di G, Qi X, et al. Substance P promotes diabetic corneal epithelial wound healing through molecular mechanisms mediated via the neurokinin-1 receptor. Diabetes. Dec 2014;63(12):4262-74. doi:10.2337/db14-0163
49. Yan D, Liu X, Guo SW. Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis. Sci Rep. Feb 25 2019;9(1):2698. doi:10.1038/s41598-019-39170-w
50. Liu X, Yan D, Guo SW. Sensory nerve-derived neuropeptides accelerate the development and fibrogenesis of endometriosis. Hum Reprod. Mar 1 2019;34(3):452-468. doi:10.1093/humrep/dey392
51. Somigliana E, Vigano P, Filardo P, Candiani M, Vignali M, Panina-Bordignon P. Use of knockout transgenic mice in the study of endometriosis: insights from mice lacking beta(2)-microglobulin and interleukin-12p40. Fertil Steril. Jan 2001;75(1):203-6. doi:S0015-0282(00)01659-9 [pii]
52. Long Q, Liu X, Qi Q, Guo SW. Chronic stress accelerates the development of endometriosis in mouse through adrenergic receptor beta2. Hum Reprod. Nov 2016;31(11):2506-2519. doi:dew237 [pii]
53. Foldenauer ME, McClellan SA, Barrett RP, Zhang Y, Hazlett LD. Substance P affects growth factors in Pseudomonas aeruginosa-infected mouse cornea. Cornea. Oct 2012;31(10):1176-88. doi:10.1097/ICO.0b013e31824d6ffd
54. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing; 2016. http://www.R-project.org/.
55. Guo SW, Ding D, Liu X. Anti-platelet therapy is efficacious in treating endometriosis induced in mouse. Reprod Biomed Online. Oct 2016;33(4):484-499.
doi:S1472-6483(16)30438-2 [pii]
56. Zhao T, Liu X, Zhen X, Guo SW. Levo-tetrahydropalmatine retards the growth of ectopic endometrial implants and alleviates generalized hyperalgesia in experimentally induced endometriosis in rats. Reprod Sci. Jan 2011;18(1):28-45. doi:1933719110381928 [pii]
57. Chen M, Li X. [Clinical application and adverse reactions of ligustrazine hydrochloride injection]. (in Chinese). Res Integrat Trad Chin West Med. 2014;4(18):211-3.
58. Maione F, De Feo V, Caiazzo E, De Martino L, Cicala C, Mascolo N. Tanshinone IIA, a major component of Salvia milthorriza Bunge, inhibits platelet activation via Erk-2 signaling pathway. J Ethnopharmacol. Sep 11 2014;155(2):1236-42. doi:10.1016/j.jep.2014.07.010
59. Cao Y, Liu X, Guo SW. Plasma High Mobility Group Box 1 (HMGB1), Osteopontin (OPN), and Hyaluronic Acid (HA) as Admissible Biomarkers for Endometriosis. Sci Rep. Jun 25 2019;9(1):9272. doi:10.1038/s41598-019-45785-w
60. Ding D, Liu X, Duan J, Guo SW. Platelets are an unindicted culprit in the development of endometriosis: clinical and experimental evidence. Hum Reprod. Apr 2015;30(4):812-32. doi:dev025 [pii]
61. Guo SW, Ding D, Geng JG, Wang L, Liu X. P-selectin as a potential therapeutic target for endometriosis. Fertil Steril. Apr 2015;103(4):990-1000 e8. doi:S0015-0282(15)00030-8 [pii]
62. Li L, Chen H, Shen A, et al. Ligustrazine inhibits platelet activation via suppression of the Akt pathway. Int J Mol Med. Jan 2019;43(1):575-582. doi:10.3892/ijmm.2018.3970
63. Cinar O, Seval Y, Uz YH, et al. Differential regulation of Akt phosphorylation in endometriosis. Reprod Biomed Online. Dec 2009;19(6):864-71.
64. Zhang H, Zhao X, Liu S, Li J, Wen Z, Li M. 17betaE2 promotes cell proliferation in endometriosis by decreasing PTEN via NFkappaB-dependent pathway. Mol Cell Endocrinol. Apr 12 2010;317(1-2):31-43.
doi:S0303-7207(09)00574-7 [pii]
65. Sharpe-Timms KL, Bruno PL, Penney LL, Bickel JT. Immunohistochemical localization of granulocyte-macrophage colony-stimulating factor in matched endometriosis and endometrial tissues. Am J Obstet Gynecol. Sep 1994;171(3):740-5. doi:0002-9378(94)90091-4 [pii]
66. Bacci M, Capobianco A, Monno A, et al. Macrophages are alternatively activated in patients with endometriosis and required for growth and vascularization of lesions in a mouse model of disease. Am J Pathol. Aug 2009;175(2):547-56. doi:S0002-9440(10)60569-X [pii]
67. Ueda M, Yamashita Y, Takehara M, et al. Survivin gene expression in endometriosis. J Clin Endocrinol Metab. Jul 2002;87(7):3452-9. doi:10.1210/jcem.87.7.8682
68. Zhang H, Li M, Zheng X, Sun Y, Wen Z, Zhao X. Endometriotic stromal cells lose the ability to regulate cell-survival signaling in endometrial epithelial cells in vitro. Mol Hum Reprod. Oct 2009;15(10):653-63. doi:10.1093/molehr/gap069
69. Guo SW. Fibrogenesis resulting from cyclic bleeding: the Holy Grail of the natural history of ectopic endometrium. Hum Reprod. Feb 6 2018;doi:4840651 [pii]
70. Guo SW, Ding D, Shen M, Liu X. Dating Endometriotic Ovarian Cysts Based on the Content of Cyst Fluid and its Potential Clinical Implications. Reprod Sci. Jul 2015;22(7):873-83. doi:10.1177/1933719115570907
71. 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. Jun 15 2016;428:1-16. doi:S0303-7207(16)30063-6 [pii]
72. 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. Oct 2016;23(10):1409-21. doi:1933719116641763 [pii]
73. Zhang Q, Liu X, Guo SW. Progressive development of endometriosis and its hindrance by anti-platelet treatment in mice with induced endometriosis. Reprod Biomed Online. Feb 2017;34(2):124-136.
doi:S1472-6483(16)30611-3 [pii]
74. Nurden AT, Nurden P, Sanchez M, Andia I, Anitua E. Platelets and wound healing. Front Biosci. May 1 2008;13:3532-48.
75. Assoian RK, Komoriya A, Meyers CA, Miller DM, Sporn MB. Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization. J Biol Chem. Jun 10 1983;258(11):7155-60.
76. Guo SW, Du Y, Liu X. Endometriosis-Derived Stromal Cells Secrete Thrombin and Thromboxane A2, Inducing Platelet Activation. Reprod Sci. Aug 2016;23(8):1044-52. doi:10.1177/1933719116630428
77. Wu X, Wang Z, Wu G, et al. Tetramethylpyrazine Induces Apoptosis and Inhibits Proliferation of Hypertrophic Scar-Derived Fibroblasts via Inhibiting the Phosphorylation of AKT. Front Pharmacol. 2020;11:602. doi:10.3389/fphar.2020.00602
78. Hu Z, Su H, Zeng Y, et al. Tetramethylpyrazine ameliorates hepatic fibrosis through autophagy-mediated inflammation. Biochem Cell Biol. Jun 2020;98(3):327-337.
79. Jin H, Lian N, Zhang F, et al. Inhibition of YAP signaling contributes to senescence of hepatic stellate cells induced by tetramethylpyrazine. Eur J Pharm Sci. Jan 1 2017;96:323-333. doi:10.1016/j.ejps.2016.10.002
80. Heard ME, Simmons CD, Simmen FA, Simmen RC. Kruppel-like factor 9 deficiency in uterine endometrial cells promotes ectopic lesion establishment associated with activated notch and hedgehog signaling in a mouse model of endometriosis. Endocrinology. Apr 2014;155(4):1532-46. doi:10.1210/en.2013-1947
81. Bullon P, Navarro JM. Inflammasome as a Key Pathogenic Mechanism in Endometriosis. Curr Drug Targets. 2017;18(9):997-1002. doi:10.2174/1389450117666160709013850
CDT-EPUB-76982 [pii]
82. Ren Y, Mu L, Ding X, Zheng W. Decreased expression of Beclin 1 in eutopic endometrium of women with adenomyosis. Arch Gynecol Obstet. Oct 2010;282(4):401-6. doi:10.1007/s00404-009-1280-0
83. Song Y, Fu J, Zhou M, et al. Activated Hippo/Yes-Associated Protein Pathway Promotes Cell Proliferation and Anti-apoptosis in Endometrial Stromal Cells of Endometriosis. J Clin Endocrinol Metab. Apr 2016;101(4):1552-61. doi:10.1210/jc.2016-1120
84. Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of Cellular Senescence. Trends Cell Biol. Jun 2018;28(6):436-453. doi:10.1016/j.tcb.2018.02.001
85. Campisi J, d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. Sep 2007;8(9):729-40. doi:10.1038/nrm2233
86. Meyer K, Hodwin B, Ramanujam D, Engelhardt S, Sarikas A. Essential Role for Premature Senescence of Myofibroblasts in Myocardial Fibrosis. J Am Coll Cardiol. May 3 2016;67(17):2018-28. doi:10.1016/j.jacc.2016.02.047
87. Zhu F, Li Y, Zhang J, et al. Senescent cardiac fibroblast is critical for cardiac fibrosis after myocardial infarction. PLoS One. 2013;8(9):e74535. doi:10.1371/journal.pone.0074535
88. Gashaw I, Hastings JM, Jackson KS, Winterhager E, Fazleabas AT. Induced endometriosis in the baboon (Papio anubis) increases the expression of the proangiogenic factor CYR61 (CCN1) in eutopic and ectopic endometria. Biol Reprod. Jun 2006;74(6):1060-6. doi:biolreprod.105.049320 [pii]
89. Absenger Y, Hess-Stumpp H, Kreft B, et al. Cyr61, a deregulated gene in endometriosis. Mol Hum Reprod. Jun 2004;10(6):399-407. doi:10.1093/molehr/gah053
gah053 [pii]
90. Kim KH, Won JH, Cheng N, Lau LF. The matricellular protein CCN1 in tissue injury repair. Journal of cell communication and signaling. Mar 2018;12(1):273-279. doi:10.1007/s12079-018-0450-x
91. Council NR. Guide for the care and use of laboratory animals. 8th ed. Washington (DC): National Academies Press (US); 2011.