Engineering the Response to Vascular Injury

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
2003 Circulation Research  
Tumor necrosis factor-␣ (TNF-␣) 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-␣, 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
more » ... 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-␣ and overexpression of E2F1 on ECs versus VSMCs. TNF-␣ 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-␣-induced marked apoptosis in contrast to the survival effect seen in ECs. Finally, these studies suggest that differential activation of NF-B may play a key role in mediating these opposing effects. Nuclear translocation and transcriptional activity of NF-B was markedly attenuated in Ad-E2F1-transduced VSMCs, whereas it remained active in similarly treated ECs when the cells were exposed to TNF-␣. These studies reveal that overexpression of Ad-E2F1 primes VSMCs to TNF-␣-induced apoptosis. Furthermore, E2F1 potentiates VSMC death by blocking antiapoptotic signaling pathway through inhibition of NF-B 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. (Circ Res. 2003;93:162-169.)
doi:10.1161/01.res.0000082980.94211.3a pmid:12829616 fatcat:qsdp5r26pbc6jlv6mvl44hxkx4