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

David A. Goukassian, Raj Kishore, Kevin Krasinski, Christine Dolan, Corinne Luedemann, Young Sup Yoon, Marianne Kearney, Allison Hanley, Hong Ma, Takayuki Asahara, Jeffrey M. Isner, Douglas W. Losordo

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Abstract

Tumor necrosis factor-α (TNF-α) 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-α, 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-α and overexpression of E2F1 on ECs versus VSMCs. TNF-α 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-α-induced marked apoptosis in contrast to the survival effect seen in ECs. Finally, these studies suggest that differential activation of NF-κB may play a key role in mediating these opposing effects. Nuclear translocation and transcriptional activity of NF-κB was markedly attenuated in Ad-E2F1-transduced VSMCs, whereas it remained active in similarly treated ECs when the cells were exposed to TNF-α. These studies reveal that overexpression of Ad-E2F1 primes VSMCs to TNF-α-induced apoptosis. Furthermore, E2F1 potentiates VSMC death by blocking antiapoptotic signaling pathway through inhibition of NF-αB 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.

Original languageEnglish
Pages (from-to)162-169
Number of pages8
JournalCirculation Research
Volume93
Issue number2
DOIs
Publication statusPublished - 2003 Jul 25

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All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

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