Key result
AdCA5 gene therapy restores ischemic limb perfusion in older mice by mobilizing angiogenic cells.
Ischemia is a stimulus for production of angiogenic cytokines that activate local vascular cells and mobilize angiogenic cells to the circulation. These responses are impaired in elderly patients with peripheral arterial disease. Hypoxia-inducible factor (HIF)-1 mediates adaptive responses to ischemia, including production of angiogenic cytokines. In this study, we demonstrate that aging and HIF-1 loss-of-function impair the expression of multiple angiogenic cytokines, mobilization of angiogenic cells, maintenance of tissue viability, and recovery of limb perfusion following femoral artery ligation. We show that HIF-1 directly activates transcription of the gene encoding stem cell factor and that mice lacking the cognate receptor C-KIT have impaired recovery from ischemia. Administration of AdCA5, an adenovirus encoding a constitutively active form of HIF-1alpha, improved the recovery of perfusion in older mice to levels similar to those in young mice. Injection of AdCA5 into nonischemic limb was sufficient to increase the number of circulating angiogenic cells. These results indicate that HIF-1 activity is necessary and sufficient for the mobilization of angiogenic cells and that HIF-1alpha gene therapy can counteract the pathological effects of aging in a mouse model of limb ischemia.
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Bosch‐Marcé et al. (2007) studied Limb ischemia. AdCA5 (adenovirus encoding constitutively active HIF-1alpha) vs. Young mice / control was evaluated on Recovery of limb perfusion and mobilization of angiogenic cells. Administration of AdCA5 (an adenovirus encoding active HIF-1alpha) improved recovery of limb perfusion in older mice to levels similar to young mice and increased circulating angiogenic cells.
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