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F6. An Egr-1 “Master Switch” for Arteriogenesis and Collateral Vessel Formation: Histologic and Perfusion Studies in Wild Type and Egr-1 Knockout Animals
Todd K Rosengart, Sorin Sarateanu, Mcgregor Leslie, James T. Beckman, Retuerto A. Mauricio, Paul Schalch, Joann Carbray, Gerald Patejunas; Evanston, IL

Background: Arteriogenesis mediating collateral vessel formation has been implicated as an important biological response mechanism to acute vascular occlusion. This premise is supported by our recent demonstration of the nearly complete absence of reperfusion after peripheral vascular ligation in transgenic mice that are homozygous negative for the early growth response-1 gene (egr-1). This gene encodes for an immediate-early response transcription factor that is upregulated by changes in vascular strain, and which in turn upregulates a number of putative angiogenic and arteriogenic growth factors. We therefore hypothesize that egr-1 may be a critical early messenger critical for inducing arteriogenesis and revascularization in the setting of acute vascular ligation.
Methods: Wild-type (wt) or Egr-1^-/- (“null”) C57 BL mice, or Sprague-Dawley rats underwent unilateral ligation of the common iliac and femoral arteries. Angiogenesis and arteriogenesis were assessed in wt and egr-1 null mice by histologic detection of endothelial cells (lectin) or smooth muscle cells (α actin). Rats underwent the direct intramuscular administration of an adenoviral vector encoding for egr-1 (AdEgr), non-coding vectors (AdNull) or saline. Distal hind limb perfusion was serially assessed using laser Doppler perfusion imaging expressed as an index of the mean perfusion in the ligated versus the non-ligated limb, and rat foot pad ischemic lesions were scored on a (1-4) grading system.
Results: Egr-1 null mice demonstrated significantly decreased hind limb perfusion 14 d post ligation compared to wild type mice (n=3/group; 0.2 ± 0.1 vs 0.5 ± 0.1, p< 0.05). Consistent with this finding, histologic analysis demonstrated an equivalent number of capillaries but a greater number of arterioles per microscopic field in wild type vs egr-null mice (22 ± 2 vs 14 ± 5, p=0.06). AdEgr injected rats (n=9) demonstrated a significantly greater average perfusion index 7 d post-ligation compared with AdNull (n=7) or saline (n=7) injected animals [0.74 ± 0.08 vs 0.58 ± 0.06 and 0.61 ± 0.06, p< 0.0002]. The average perfusion index was nearly normalized in AdEgr injected rats 21 d post-ligation compared to the presence of a persistent perfusion deficit in AdNull and saline injected animals [0.95 ± 0.1 vs 0.75 ± 0.01 and 0.77 ± 0.018; p< 0.02]. Consistent with these findings, AdEgr injected rats demonstrated significantly less severe ischemic foot pad lesions 21 d post-ligation compared with AdNull animals (p<0.004).
Conclusion: These data suggest the importance of egr-1 as a critical, potentially therapeutic, mediator of revascularization following vascular occlusion, and implicate arteriogenesis (collateral vessel formation) as a critical component of this process.

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