Spatial and Temporal Changes in Gene Expression and Blood Flow Recovery after Chronic and Acute Hindlimb Ischemia in the Mouse

Abstract

Background Current mechanistic studies of critical limb ischemia are performed in mouse models of acute hindlimb ischemia that are not clinically relevant to most cases of human chronic critical limb ischemia. To overcome this limitation, we have developed the first mouse model of chronic hindlimb ischemia and compared the spatial and temporal change in gene expression and blood flow recovery to that seen in a model of acute hindlimb ischemia. Methods and Results Chronic hindlimb ischemia was induced by placing ameroid constrictors on the proximal and distal left femoral artery and ligation of the femoral artery branches. Blood perfusion and gene expression levels were measured in the thigh muscle and calf muscle of both models by laser Doppler and Q-RT-PCR. Hypoxia related genes increased significantly in the calf, but not in the thigh. Shear stress related genes and inflammatory genes were upregulated immediately in the thigh after induction of acute, but not chronic ischemia. This is consistent with the less blood flow recovery in chronic versus acute ischemia. Conclusion Spatial and temporal changes of gene expression and blood flow recovery are different in models of acute and chronic limb ischemia. After acute ischemia, up regulation of shear stress and inflammatory genes in the thigh muscle appear to contribute to collateral artery enlargement and may be responsible for the more rapid and complete blood flow recovery after induction of acute versus chronic ischemia. The molecular mechanisms that regulate collateral artery enlargement and blood flow recovery are distinct after chronic and acute ischemia.