Egr‑1 promotes the proliferation and migration of vascular smooth muscle cells by transcriptionally activating Egr‑2 in arteriovenous fistulas

Hu,Ke; Bu,Shichen; Guo,Yi; Li,Yuxuan; Yu,Shiwen; Wang,Lulu; Cai,Chuanqi; Li,Yiqing; Liu,Xin; Huang,Hegui; Wang,Weici

doi:10.3892/ijmm.2025.5568

Egr‑1 promotes the proliferation and migration of vascular smooth muscle cells by transcriptionally activating Egr‑2 in arteriovenous fistulas

Authors:
- Ke Hu
- Shichen Bu
- Yi Guo
- Yuxuan Li
- Shiwen Yu
- Lulu Wang
- Chuanqi Cai
- Yiqing Li
- Xin Liu
- Hegui Huang
- Weici Wang
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Affiliations: Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China, Department of Cardiology, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361006, P.R. China, Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430022, P.R. China, Department of Pharmacy, Wuhan No. 1 Hospital, Wuhan, Hubei 430022, P.R. China
Published online on: June 23, 2025 https://doi.org/10.3892/ijmm.2025.5568
Article Number: 127

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Abstract

Arteriovenous fistulas (AVFs) are preferred access points for hemodialysis. The present study aimed to investigate the function of early growth response‑1 (Egr‑1) in the proliferation and migration of smooth muscle cells (SMCs) and assess its potential as a new therapeutic target for AVF treatment. A comprehensive analysis combining public data‑source mining, human tissue collection, animal studies, cell culture experiments and various molecular biology techniques was conducted. The public dataset GSE119296 was used for immunohistochemical analyses of human AVF stenosis samples. SMC‑specific Egr‑1 knockout mice and various in vitro assays on primary rat vascular SMCs were used to evaluate the effect of Egr‑1 on the functional capacity of SMCs. RNA sequencing and chromatin immunoprecipitation sequencing was performed. Egr‑1 was upregulated in human AVF stenosis samples and cultured SMCs. Knockout of Egr‑1 in mice mitigated AVF outflow tract stenosis, improved flow dynamics and diminished neointima formation. In vitro, Egr‑1 ablation reduced SMC proliferation and migration; Egr‑1 transcriptionally activated Egr‑2. Increased Egr‑1 expression facilitated SMC proliferation and migration through Egr‑2 regulation, contributing to AVF stenosis. Consequently, targeting Egr‑1 may offer a novel therapeutic approach for managing AVF intimal hyperplasia and improving AVF patency and function in patients with end‑stage renal disease.

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1	Vachharajani TJ, Taliercio JJ and Anvari E: New devices and technologies for hemodialysis vascular access: A review. Am J Kidney Dis. 78:116–124. 2021. View Article : Google Scholar : PubMed/NCBI
2	Agarwal AK, Haddad NJ, Vachharajani TJ and Asif A: Innovations in vascular access for hemodialysis. Kidney Int. 95:1053–1063. 2019. View Article : Google Scholar : PubMed/NCBI
3	Brahmbhatt A, Remuzzi A, Franzoni M and Misra S: The molecular mechanisms of hemodialysis vascular access failure. Kidney Int. 89:303–316. 2016. View Article : Google Scholar : PubMed/NCBI
4	Khachigian LM: Early growth response-1, an integrative sensor in cardiovascular and inflammatory disease. J Am Heart Assoc. 10:e0235392021. View Article : Google Scholar : PubMed/NCBI
5	Khachigian LM: Early growth response-1 in the pathogenesis of cardiovascular disease. J Mol Med (Berl). 94:747–753. 2016. View Article : Google Scholar : PubMed/NCBI
6	Yan SF, Harja E, Andrassy M, Fujita T and Schmidt AM: Protein kinase C beta/early growth response-1 pathway: A key player in ischemia, atherosclerosis, and restenosis. J Am Coll Cardiol. 48 (Suppl 1):A47–A55. 2006. View Article : Google Scholar : PubMed/NCBI
7	van Albada ME, Bartelds B, Wijnberg H, Mohaupt S, Dickinson MG, Schoemaker RG, Kooi K, Gerbens F and Berger RM: Gene expression profile in flow-associated pulmonary arterial hypertension with neointimal lesions. Am J Physiol Lung Cell Mol Physiol. 298:L483–L491. 2010. View Article : Google Scholar : PubMed/NCBI
8	Martinez L, Rojas MG, Tabbara M, Pereira-Simon S, Santos Falcon N, Rauf MA, Challa A, Zigmond ZM, Griswold AJ, Duque JC, et al: The transcriptomics of the human vein transformation after arteriovenous fistula anastomosis uncovers layer-specific remodeling and hallmarks of maturation failure. Kidney Int Rep. 8:837–850. 2023. View Article : Google Scholar : PubMed/NCBI
9	Hu K, Guo Y, Li Y, Zhou S, Lu C, Cai C, Yang H, Li Y and Wang W: Identification and validation of PTGS2 gene as an oxidative stress-related biomarker for arteriovenous fistula failure. Antioxidants (Basel). 13:52023. View Article : Google Scholar : PubMed/NCBI
10	Yang B, Vohra PK, Janardhanan R, Misra KD and Misra S: Expression of profibrotic genes in a murine remnant kidney model. J Vasc Interv Radiol. 22:1765–1772.e1. 2011. View Article : Google Scholar : PubMed/NCBI
11	Cai C, Kilari S, Zhao C, Simeon ML, Misra A, Li Y, van Wijnen AJ, Mukhopadhyay D and Misra S: Therapeutic effect of adipose derived mesenchymal stem cell transplantation in reducing restenosis in a murine angioplasty model. J Am Soc Nephrol. 31:1781–1795. 2020. View Article : Google Scholar : PubMed/NCBI
12	Kilari S, Cai C, Zhao C, Sharma A, Chernogubova E, Simeon M, Wu CC, Song HL, Maegdefessel L and Misra S: The role of microRNA-21 in venous neointimal hyperplasia: Implications for targeting miR-21 for VNH treatment. Mol Ther. 27:1681–1693. 2019. View Article : Google Scholar : PubMed/NCBI
13	Janardhanan R, Yang B, Kilari S, Leof EB, Mukhopadhyay D and Misra S: The role of repeat administration of adventitial delivery of lentivirus-shRNA-Vegf-A in arteriovenous fistula to prevent venous stenosis formation. J Vasc Interv Radiol. 27:576–583. 2016. View Article : Google Scholar : PubMed/NCBI
14	Zamboli P, Fiorini F, D'Amelio A, Fatuzzo P and Granata A: Color doppler ultrasound and arteriovenous fistulas for hemodialysis. J Ultrasound. 17:253–263. 2014. View Article : Google Scholar : PubMed/NCBI
15	Chomczynski P and Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 162:156–159. 1987. View Article : Google Scholar : PubMed/NCBI
16	Dickinson MG, Kowalski PS, Bartelds B, Borgdorff MA, van der Feen D, Sietsma H, Molema G, Kamps JA and Berger RM: A critical role for Egr-1 during vascular remodelling in pulmonary arterial hypertension. Cardiovasc Res. 103:573–584. 2014. View Article : Google Scholar : PubMed/NCBI
17	Xie X, Li S, Zhu Y, Liu L, Ke R, Wang J, Yan X, Yang L, Gao L, Zang W and Li M: Egr-1 mediates leptin-induced PPARγ reduction and proliferation of pulmonary artery smooth muscle cells. Mol Biol Cell. 29:356–362. 2018. View Article : Google Scholar : PubMed/NCBI
18	Vazquez-Padron RI, Mateu D, Rodriguez-Menocal L, Wei Y, Webster KA and Pham SM: Novel role of Egr-1 in nicotine-related neointimal formation. Cardiovasc Res. 88:296–303. 2010. View Article : Google Scholar : PubMed/NCBI
19	Wu X, Cheng J, Li P, Yang M, Qiu S, Liu P and Du J: Mechano-sensitive transcriptional factor Egr-1 regulates insulin-like growth factor-1 receptor expression and contributes to neointima formation in vein grafts. Arterioscler Thromb Vasc Biol. 30:471–476. 2010. View Article : Google Scholar : PubMed/NCBI
20	Hinze AV, Mayer P, Harst A and von Kügelgen I: Adenosine A(3) receptor-induced proliferation of primary human coronary smooth muscle cells involving the induction of early growth response genes. J Mol Cell Cardiol. 53:639–645. 2012. View Article : Google Scholar : PubMed/NCBI
21	Yin P, Navarro A, Fang F, Xie A, Coon JS, Richardson C and Bulun SE: Early growth response-2 expression in uterine leiomyoma cells: Regulation and function. Fertil Steril. 96:439–444. 2011. View Article : Google Scholar : PubMed/NCBI