Engineering the response to vascular injury: divergent effects of deregulated E2F1 expression on vascular smooth muscle cells and endothelial cells result in endothelial recovery and inhibition of neointimal growth

Circ Res. 2003 Jul 25;93(2):162-9. doi: 10.1161/01.RES.0000082980.94211.3A. Epub 2003 Jun 26.


Tumor necrosis factor-alpha (TNF-alpha) is expressed locally in the vessel wall after angioplasty and induces growth arrest and apoptosis in endothelial cells (ECs), thereby delaying reendothelialization. Prior studies have shown that direct antagonism of TNF-alpha, using a systemically administered soluble receptor, can enhance endothelial recovery and reduce neointimal thickening. These studies have also shown that downregulation of the transcription factor E2F1 was a key mechanism of TNF's effect on ECs. We now show that Ad-E2F1 overexpression at sites of balloon injury accelerates functional endothelial recovery, consistent with the prior in vitro findings. Moreover these studies also reveal divergent effects of TNF-alpha and overexpression of E2F1 on ECs versus VSMCs. TNF-alpha exposure of VSMCs had no affect on proliferation or apoptosis, in contrast to the effect seen in ECs. In Ad-E2F1-transduced VSMCs, however, TNF-alpha-induced marked apoptosis in contrast to the survival effect seen in ECs. Finally, these studies suggest that differential activation of NF-kappaB may play a key role in mediating these opposing effects. Nuclear translocation and transcriptional activity of NF-kappaB was markedly attenuated in Ad-E2F1-transduced VSMCs, whereas it remained active in similarly treated ECs when the cells were exposed to TNF-alpha. These studies reveal that overexpression of Ad-E2F1 primes VSMCs to TNF-alpha-induced apoptosis. Furthermore, E2F1 potentiates VSMC death by blocking antiapoptotic signaling pathway through inhibition of NF-kappaB activation. The divergent responses of VSMCs and ECs to E2F1 overexpression provide unique therapeutic possibilities: simultaneously targeting the cell cycle of two different cell types, within same tissue microenvironment resulting in opposite and biologically complimentary effects.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Apoptosis
  • Carotid Artery Injuries / metabolism*
  • Carotid Artery Injuries / pathology
  • Caspases / metabolism
  • Cattle
  • Cell Cycle Proteins*
  • Cell Division / drug effects
  • Cell Division / genetics
  • Cells, Cultured
  • DNA-Binding Proteins*
  • Disease Models, Animal
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism*
  • Gene Expression Regulation
  • Genes, Reporter
  • Humans
  • Hyperplasia / pathology
  • I-kappa B Proteins / metabolism
  • Mice
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / pathology
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Recovery of Function
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tunica Intima / growth & development*
  • Tunica Intima / injuries
  • Tunica Intima / pathology


  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • E2f1 protein, mouse
  • E2f1 protein, rat
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Nfkbia protein, rat
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Caspases