Homozygous deletion of early growth response 1 gene and critical limb ischemia after vascular ligation in mice: Evidence for a central role in vascular homeostasis
Homozygous deletion of early growth response 1 gene and critical limb ischemia after vascular ligation in mice: Evidence for a central role in vascular homeostasis
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DOI：
10.1016/j.jtcvs.2004.02.036
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发表时间：
2004-10-01
影响因子：
6
通讯作者：
Rosengart, TK
中科院分区：
文献类型：
--
作者：
Schalch, P;Patejunas, G;Rosengart, TK
背景资料：早期生长反应1基因（Egr 1）编码一种即时至早期反应转录因子，该转录因子通过血管紧张和缺氧的变化而上调，进而上调许多血管生成生长因子的下游表达。因此，我们假设早期生长反应1可能是急性血管闭塞情况下控制血运重建的关键早期信使。Egr 1基因缺陷的C57 BL/6小鼠（敲除）和他们的野生型同窝出生的伙伴进行结扎和切除股动脉与或不与先前的管理2.7 × 10（9）编码血管内皮生长因子基因（VEGF）或Egr 1的腺病毒载体的颗粒单位。远端后肢灌注连续测量这些动物与激光多普勒perfusion imaging.Results：野生型小鼠（n = 9）几乎完全恢复后肢灌注结扎后35天。相反，所有未注射Egr 1基因敲除小鼠（n = 5）在结扎后1 - 4天出现严重的同侧肢体坏死（P < .0001）。注射VEGF载体的Egr 1敲除小鼠（n = 4）在结扎后第28天表现出相对于基线的灌注显著改善，这种改善持续到结扎后第35天（P <0.05）。Egr 1基因敲除动物（n = 7）在结扎后第4天与VEGF基因敲除动物相比，后肢血流灌注部分恢复（P <0.01），并持续到第35天。结论：这些发现表明早期生长反应1在小鼠和其他哺乳动物血管闭塞的再灌注反应中起着关键作用。
Background: The early growth response 1 gene (Egr1) encodes for an immediate to early response transcription factor that is upregulated by changes in vascular strain and hypoxia and in turn upregulates the downstream expressions of a number of angiogenic growth factors. We therefore hypothesized that early growth response 1 may be a critical early messenger governing revascularization in the setting of acute vascular occlusions.Methods: C57 BL/6 mice deficient in the Egr1 gene (knockout) and their wild-type litter mates underwent ligation and excision of the femoral artery with or without the previous administration of 2.7 x 10(9) particle units of an adenoviral vector coding for the vascular endothelial growth factor gene (VEGF) or Egr1. Distal hind limb perfusion was serially measured in these animals with laser Doppler perfusion imaging.Results: Wild-type mice (n = 9) had nearly complete restitution of hind limb perfusion by day 35 after ligation. In contrast, all noninjected Egr1 knockout mice (n = 5) had severe ipsilateral limb necrosis develop between 1 and 4 days after ligation (P < .0001). Egr1 knockout mice injected with VEGF vector (n = 4) demonstrated significantly improved perfusion relative to baseline by postligation day 28, which persisted to postligation day 35 (P < .05). Egr1 knockout animals injected with Egr1 vector (n = 7) demonstrated a partial recovery of hind limb perfusion relative to VEGF vector-treated knockout animals at postligation day 4 (P < .01), which persisted to day 35.Conclusions: These findings suggest that early growth response 1 plays a pivotal role in reperfusion responses to vascular occlusion in mice and possibly other mammals.