Abstract
BackgroundPeripheral arterial disease (PAD) is a common disease accounting for about 12% of the adult population, and causes significant morbidity and mortality. Therapeutic angiogenesis using angiogenic factors has been considered to be a potential treatment option for PAD patients. In this study, we assessed the potential of a new angiogenic factor AGGF1 for therapeutic angiogenesis in a critical limb ischemia model in mice for PAD.Methods and ResultsWe generated a unilateral hindlimb ischemia model in mice by ligation of the right common iliac artery and femoral artery. Ischemic mice with intrasmuscular administration of DNA for an expression plasmid for human AGGF1 (AGGF1 group) resulted in increased expression of both AGGF1 mRNA and protein after the administration compared with control mice with injection of the empty vector (control group). Color PW Doppler echocardiography showed that the blood flow in ischemic hindlimbs was significantly increased in the AGGF1 group compared to control mice at time points of 7, 14, and 28 days after DNA administration (n = 9/group, P = 0.049, 0.001, and 0.001, respectively). Increased blood flow in the AGGF1 group was correlated to increased density of CD31-positive vessels and decreased necrosis in muscle tissues injected with AGGF1 DNA compared with the control tissue injected with the empty vector. Ambulatory impairment was significantly reduced in the AGGF1 group compared to the control group (P = 0.004). The effect of AGGF1 was dose-dependent. At day 28 after gene transfer, AGGF1 was significantly better in increasing blood flow than FGF-2 (P = 0.034), although no difference was found for tissue necrosis and ambulatory impairment.ConclusionsThese data establish AGGF1 as a candidate therapeutic agent for therapeutic angiogenesis to treat PAD.
Highlights
Peripheral arterial disease (PAD) is caused by atherosclerosis, which results in progressive narrowing and occlusion of the peripheral arteries and inhibits blood flow to the lower extremities [1,2]
We have demonstrated that AGGF1 promotes angiogenesis as potentially as vascular endothelial growth factor A (VEGF) in a chicken embryo angiogenesis assay [21]
Previous reports by others demonstrated that the efficiency of gene transfer by direct injection of DNA for an expression plasmid was determined by the amount of plasmid DNA and the injection volume [24]
Summary
Peripheral arterial disease (PAD) is caused by atherosclerosis, which results in progressive narrowing and occlusion of the peripheral arteries and inhibits blood flow to the lower extremities [1,2]. The prevalence of PAD is increasing in the modern aging society, and reaches about 12% of the adult population [3,4]. In patients with PAD the prevalence of coronary artery disease (CAD) is about 46% to 71% [1,9,10], and at least 10% of them suffered cerebrovascular disease [1,2,11,12]. Peripheral arterial disease (PAD) is a common disease accounting for about 12% of the adult population, and causes significant morbidity and mortality. Therapeutic angiogenesis using angiogenic factors has been considered to be a potential treatment option for PAD patients. We assessed the potential of a new angiogenic factor AGGF1 for therapeutic angiogenesis in a critical limb ischemia model in mice for PAD
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