EGR2 promotes vascular smooth muscle cell differentiation and proliferation in outward remodeling during arteriovenous fistula maturation.

Arteriovenous fistula (AVF) maturation is characterized by outward remodeling presented mainly as wall thickening and lumen enlargement, probably mediated by increased differentiated vascular smooth muscle cells (VSMCs) and extracellular matrix (ECM) deposits, at least in part. Our previous study revealed that the highly conserved transcription factor early growth response protein 2 (EGR2) promoted renal tubular epithelial cell differentiation and ECM accumulation. Here, we found that EGR2 expression was enhanced in venous outflow tracts from end-stage renal disease (ESRD) patients and mice with AVF surgery accompanied by a thickened venous wall and enlarged lumen. Then, the knockdown of EGR2 could inhibit AVF maturation while EGR2 overexpression further promoted outward remodeling in AVF mice with adeno-associated virus (AAV) administration regulated by differentiated VSMCs and ECM deposition. Mechanistically, gene deletion of EGR2 inhibited c-Myc possibly by binding to the promoter region of the insulin-like growth factor 2 binding protein 2 (IGF2BP2) gene. Moreover, EGR2 was upregulated by histone deacetylase 4 (HDAC4) which probably negatively regulated transcription factor c-Jun, the latter was reported to antagonize the effect of EGR2. Thus, we speculated that EGR2 is upregulated by HDAC4 possibly by negatively regulating c-Jun and promoting outward remodeling through the IGF2BP2/ c-Myc signaling axis during AVF maturation.