Mechano-sensitive transcriptional factor Egr-1 regulates insulin-like growth factor-1 receptor expression and contributes to neointima formation in vein grafts.
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.


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.


CONCLUSIONS
Egr-1 is a mechano-sensitive transcriptional factor that stimulates IGF-1R transcription, resulting in vascular remodeling of vein grafts.
Wu
Xiaoqian
X
Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
Cheng
Jizhong
J
Li
Ping
P
Yang
Min
M
Qiu
Shulan
S
Liu
Peiqing
P
Du
Jie
J
D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D004548:Elasticity; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D017539:Tunica Intima / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology; D014680:Veins / Q000378:metabolism / Q000503:physiopathology / Q000637:transplantation*
D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017526:Receptor, IGF Type 1