Mechano-Sensitive Transcriptional Factor Egr-1 Regulates Insulin-Like Growth Factor-1 Receptor Expression and Contributes to Neointima Formation in Vein Grafts

Abstract

Objective— Vein grafts in a coronary bypass or a hemodialysis access often develop obliterative growth of the neointima. We previously reported that the mechanical stretch-activated insulin-like growth factor-1 receptor (IGF-1/IGF-1R) pathway plays an important role in this remodeling. However, the transcriptional mechanism(s) regulating IGF-1R expression and neointima formation have not been identified. Methods and Results— Deletion and site-specific mutagenesis analysis of IGF-1R promoter identified that the minimal mechano-responsive promoter element (−270–−130) contains 2 consensus sequences for binding of early growth reponse-1 (Egr-1) transcriptional factor. Mechanical stretch stimulated both Egr-1 mRNA (4.6-fold) and protein (5.2-fold) in vascular smooth muscle cells. Interposition of a vein into an artery increased Egr-1 mRNA (7.8±2.6-fold vs sham). In vascular smooth muscle cells isolated from Egr-1 knockout mice, mechanical stretch could not increase IGF-1R, and vascular smooth muscle cells proliferation was decreased by 47% compared to wild-type cells. Importantly, the neointima area was reduced by at least 50%, and the lumen-to-media ratio increased by 55% in vein grafts of Egr-1 knockout mice compared with results of wild-type mice. Conclusion— Egr-1 is a mechano-sensitive transcriptional factor that stimulates IGF-1R transcription, resulting in vascular remodeling of vein grafts.