title: 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.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Cardiovascular Research, St Elizabeth's Medical Center, Boston, Mass, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Goukassian
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.forename: Kevin
authors.initials: K
authors.lastname: Krasinski
authors.forename: Christine
authors.initials: C
authors.lastname: Dolan
authors.forename: Corinne
authors.initials: C
authors.lastname: Luedemann
authors.forename: Young-sup
authors.initials: YS
authors.lastname: Yoon
authors.forename: Marianne
authors.initials: M
authors.lastname: Kearney
authors.forename: Allison
authors.initials: A
authors.lastname: Hanley
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asahara
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Isner
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D020212:Carotid Artery Injuries / Q000378:metabolism* / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D002417:Cattle; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D006965:Hyperplasia / Q000473:pathology; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D017539:Tunica Intima / Q000254:growth & development* / Q000293:injuries / Q000473:pathology
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; C493755:E2f1 protein, rat; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C000606206:Nfkbia protein, rat; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D020169:Caspases