An Egr-1 master switch for arteriogenesis: Studies in Egr-1 homozygous negative and wild-type animals

Background: Arteriogenesis has been implicated as an important biologic response to acute vascular occlusion. The early growth response 1 (Egr-1) gene encodes an immediate-early response transcription factor that is upregulated by changes in vascular strain and that in turn upregulates a number of putative angiogenic and arteriogenic growth factors. We therefore hypothesized that early growth response 1 might be a critical arteriogenic messenger that induces revascularization in the setting of acute vascular occlusions. Methods: Wild-type or Egr-1^-/- (null) C57 BL mice, or Sprague-Dawley rats, underwent unilateral iliofemoral artery excision and subsequent analyses for angiogenesis and arteriogenesis through cell-specific immunohistochemistry. Rats were also administered an adenoviral vector encoding for Egr-1 (AdEgr group), noncoding vectors (AdNull group), or saline, after which these animals were assessed by means of serial laser Doppler perfusion imaging and morphologic examination of rat foot-pad ischemic lesions. Results: Egr-1 wild-type mice demonstrated an equivalent number of capillaries but a greater number of arterioles following excision versus Egr-1 null mice. AdEgr group rats demonstrated greater distal perfusion from 7 to 21 days after excision compared with control animals (P < .02), which approximated normal perfusion at 21 days after excision. AdEgr group rats also demonstrated greater arteriolar density and less severe ischemic foot-pad lesions than control animals. Conclusion: These data suggest the importance of Egr-1 as a critical and potentially therapeutic mediator of revascularization after vascular occlusion and implicate arteriogenesis (collateral vessel formation) as a critical component of this process.