Effects of SU5416 on angiogenesis and the ERK-VEGF/MMP-9 pathway in rat endometriosis.
Efecto del SU5416 sobre la angiogenesis y la via ERK-VEGF/ MMP-9 en la endometriosis de ratas.
Keywords:
angiogenesis, endometriosis, ERK-VEGF/MMP-9 pathway, SU5416
Abstract
SU5416 is a small molecule vascular endothelial growth factor (VEGF) receptor signal transduction inhibitor, which can block the VEGF receptor autophosphorylation and inhibit receptor tyrosine kinase signal transduction, thereby reducing VEGF activity. However, there are few reports about the correlation of SU5416 to the occurrence and angiogenesis in endometriosis. In this study, we observed the effects of VEGF receptor inhibitor SU5416 on angiogenesis in endometriosis in rats. Thirty female specific-pathogen- free Sprague-Dawley rats were randomly divided into sham operation group (SOG), model group (MG), and SU5416 group (n=10 for each group). In the SOG, only the uterus was cut and sutured, and endometriosis models were established in the MG and SU5416 group by autologous transplantation. The SU5416 group was injected with 15 mg/kg SU5416 intraperitoneally, and the SOG and MG were intraperitoneally injected with an equal volume of normal saline for 6 weeks. The volume of ectopic lesions was lower in the SU5416 group at 42 d postoperatively than in the MG (p<0.05). The proportion of CD31-positive cells in the endometrial tissue of the SU5416 group was lower than that of the MG (p<0.05); angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), laminin-5γ2 (LN-5γ2) and phosphorylation of ERK (P-ERK), VEGF, matrix metalloproteinase (MMP)-2, and MMP-9 protein expressions were lower in the SU5416 group than in the MG (p<0.05). VEGF receptor inhibitor SU5416 can inhibit endometriosis angiogenesis and reduce inflammatory response in rats, and its mechanism of action may be related to the down-regulation of the ERK-VEGF/MMP-9 path-way expression.
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References
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Jin Z, Zhang Y, Li J, Lv S, Zhang L, Feng Y. Endometriosis stem cell sources and potential therapeutic targets: literature review and bioinformatics analysis. Regen Med 2021; 16(10): 949-962. https://doi. org/10.2217/rme-2021-0039.
Ding L, Yang L, Ren C, Zhang H, Lu J, Wang S, Wu Z, Yang Y. A review of aberrant DNA methylation and epigenetic agents targeting DNA methyltransferases in endometriosis. Curr Drug Targets 2020; 21(11): 1047-1055. https://doi.org/10.2174/1389450121666200228112344.
Doroftei B, Ilie OD, Balmus IM, Ciobica A, Maftei R, Scripcariu I, Simionescu G, Grab D, Stoian I, Ilea C. Molecular and clinical insights on the complex interaction between oxidative stress, apoptosis, and endobiota in the pathogenesis of endometriosis. Diagnostics (Basel) 2021; 11(8): 1434. https://doi.org/10.3390/diag nostics11081434.
Mesquita J, Castro de Sousa JP, Vaz-Pereira S, Neves A, Tavares-Ratado P, Santos FM, Passarinha LA, Tomaz CT. VEGF-B levels in the vitreous of diabetic and non-diabetic patients with ocular diseases and its correlation with structural parameters. Med Sci (Basel). 2017; 5(3): 17. https://doi.org/10.3390/medsci5030017.
Pergialiotis V, Fanaki M, Bellos I, Stefanidis K, Loutradis D, Daskalakis G. The impact of vascular endothelial growth factor single nucleotide polymorphisms in the development and severity of endometriosis: A systematic review of the literature. J Gynecol Obstet Hum Reprod 2020; 101732. https://doi.org/10.1016/j.jogoh.2020.101732.
Huang H. Matrix Metalloproteinase-9 (MMP-9) as a cancer biomarker and MMP-9 biosensors: recent advances. Sensors (Basel) 2018; 18(10): 3249. https://doi.org/1 0.3390/s18103249.
Ye C, Sweeny D, Sukbuntherng J, Zhang Q, Tan W, Wong S, Madan A, Ogilvie B, Parkinson A, Antonian L. Distribution, metabolism, and excretion of the anti-angiogenic compound SU5416. Toxicol In Vitro 2006; 20(2): 154-162. https://doi. org/10.1016/j.tiv.2005.06.047.
Sakao S, Tatsumi K. The effects of antian giogenic compound SU5416 in a rat model of pulmonary arterial hypertension. Respiration 2011; 81(3): 253-261. https://doi. org/10.1159/000322011.
Bahrami A, Ayen E, Razi M, Behfar M. Effects of atorvastatin and resveratrol against the experimental endometriosis; evidence for glucose and monocar- boxylate transporters, neoangiogenesis. Life Sci 2021; 272: 119230. https://doi. org/10.1016/j.lfs.2021.119230.
Rashidi BH, Sarhangi N, Aminimoghaddam S, Haghollahi F, Naji T, Amoli MM, Shahrabi-Farahani M. Association of vascular endothelial growth factor (VEGF) Gene polymorphisms and expression with the risk of endometriosis: a case- control study. Mol Biol Rep 2019; 46(3): 3445-3450. https://doi.org/10.1007/s11033-019-04807-6.
Li YZ, Wang LJ, Li X, Li SL, Wang JL, Wu ZH, Gong L, Zhang XD. Vascular endothelial growth factor gene polymorphisms contribute to the risk of endometriosis: an updated systematic review and meta- analysis of 14 case-control studies. Genet Mol Res 2013;12(2): 1035-1044. https:// doi.org/10.4238/2013.April.2.20.
Qiu JJ, Lin XJ, Zheng TT, Tang XY, Zhang Y, Hua KQ. The exosomal long noncoding RNA aHIF is upregulated in serum from patients with endometriosis and promotes angiogenesis in endometriosis. Reprod Sci 2019; 26(12): 1590-1602. https://doi. org/10.1177/1933719119831775.
Liu S, Xin X, Hua T, Shi R, Chi S, Jin Z, Wang H. Efficacy of anti-VEGF/VE- GFR agents on animal models of endometriosis: A systematic review and meta-analysis. PLoS One. 2016; 11(11): e0166658. https://doi.org/10.1371/journal.pone.0166658.
Mendel DB, Laird AD, Smolich BD, Blake RA, Liang C, Hannah AL, Shaheen RM, Ellis LM, Weitman S, Shawver LK, Cherrington JM. Development of SU5416, a selective small molecule inhibitor of VEGF receptor tyrosine kinase activity, as an anti-angiogenesis agent. Anticancer Drug Des 2000; 15(1): 29-41.
Guo YJ, Pan WW, Liu SB, Shen ZF, Xu Y, Hu LL. ERK/MAPK signalling pathway and tumorigenesis. Exp Ther Med 2020; 19(3):1997-2007. https://doi.org/10.3892/etm.2020.8454.
Pashirzad M, Khorasanian R, Fard MM, Arjmand MH, LangariH, Khazaei M, Soleimanpour S, Rezayi M, Ferns GA, Hassanian SM, Avan A. The therapeutic potential of MAPK/ ERK inhibitors in the treatment of colorectal cancer. Curr Cancer Drug Targets 2021; 21(11): 932-943. https://doi.org/10.2174/1568009621666211103113339.
Li Y, Fang L, Yu Y, Shi H, Wang S, Li Y, Ma Y, Yan Y, Sun YP. Association between vascular endothelial growth factor gene polymorphisms and PCOS risk: a meta- analysis. Reprod Biomed Online 2020; 40(2): 287-295. https://doi.org/10.1016/j. rbmo.2019.10.018.
Zhang H. Expression and significance of MEK-5, ERK5, p-ERK, VEGF and MMP-9 in endometriosis [Master’s thesis]. Tianjin: Tianjin Medical University; 2013.
Mondal S, Adhikari N, Banerjee S, Amin SA, Jha T. Matrix metalloprotei- nase-9 (MMP-9) and its inhibitors in cancer: A minireview. Eur J Med Chem. 2020;194:112260. https://doi.org/10.1016/j.ejmech.2020.112260.
Dong H, Diao H, Zhao Y, Xu H, Pei S, Gao J, Wang J, Hussain T, Zhao D, Zhou X, Lin D. Overexpression of matrix metallo proteinase-9 in breast cancer cell lines remarkably increases the cell malignancy largely via activation of transforming growth factor beta/SMAD signalling. Cell Prolif 2019; 52(5): e12633. https://doi. org/10.1111/cpr.12633.
Chen Z, Xu DY, Yang K. Association of ERK- VEG FMMP-9 signaling pathway with proliferation and angiogenesis in rectal cancer cells. Genomics and Applied Biology 2019; 38: 5828-5835. https://doi: 10.13417/j.gab.038.005828.
Guo ML, Wang CE, Duan YM, Wang JG. Gecko crude peptides inhibit migration and lymphangiogenesis by down regulating the expression of VEGF-C in human hepatocellular carcinoma cells and human lymphatic endothelial cells. Chin J Pharmacol Toxicol 2017; 31(10): 958-959. https://doi: 10.3867/j.issn.1000-3002.2017.10.025
Yilmaz B, Kilic S, Aksakal O, Ertas IE, Tanrisever GG, Aksoy Y, Lortlar N, Kelekci S, Gungor T. Melatonin causes regression of endometriotic implants in rats by modulating angiogenesis, tissue levels of antioxidants and matrix metalloproteinases. Arch Gynecol Obstet 2015; 292(1):209-216. https://doi.org/10.1007/s00404-014-3599-4.
Published
2023-11-20
How to Cite
Zhao, D., Bao, Q., Chen, L., & Zheng, L. (2023). Effects of SU5416 on angiogenesis and the ERK-VEGF/MMP-9 pathway in rat endometriosis.: Efecto del SU5416 sobre la angiogenesis y la via ERK-VEGF/ MMP-9 en la endometriosis de ratas. Investigación Clínica, 64(4), 482-494. https://doi.org/10.54817/IC.v64n4a5
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Original Works
