Abstract
Purpose Peripheral artery disease (PAD) causes narrowing of arteries in the limbs, leading to tissue ischemia, gangrene, and eventually limb amputation. The presence of diabetes greatly exacerbates the course of PAD, accounting for the majority of lower limb amputations. Therapeutic strategies focussing on macrovascular repair are less effective in diabetic patients where smaller vessels are affected, and proangiogenic therapies offer a viable adjunct to improve vascularisation in these at risk individuals. The purpose of the current study was to assess the proangiogenic effects of drugs routinely used to treat cardiovascular disease in a diabetic murine model of hind limb ischemia longitudinally using multimodal imaging. Procedures Diabetic mice underwent surgical intervention to induce hind limb ischemia and were treated with simvastatin, metformin, or a combination orally for 28 days and compared to diabetic and nondiabetic mice. Neovascularisation was assessed using [18F]FtRGD PET imaging, and macrovascular volume was assessed by quantitative time of flight MRI. At each imaging time point, VEGF expression and capillary vessel density were quantified using immunohistochemical analysis, and functional recovery and disease progression were assessed. Results Combined use of simvastatin and metformin significantly increased neovascularisation above levels measured with either treatment alone. Early angiogenic events were accurately assessed using PET [18F]FtRGD, showing maximal retention in the ischemic hind limb by day 8, which translated to a sustained increase in vascular volume at later time points. Immunohistochemical analysis shows that combined therapy significantly increased VEGF expression and capillary density (CD31+) in a similar time course and also slowed disease progression while simultaneously improving functional foot use. Conclusions Combined treatment with simvastatin and metformin led to a significant improvement in limb angiogenesis, vascular volume, and sustained functional recovery in a diabetic murine model of HLI. PET imaging with [18F]FtRGD provides a robust method for early detection of these proangiogenic effects preclinically and may be useful for the assessment of proangiogenic therapies used clinically to treat diabetic PAD patients.
Highlights
Peripheral artery disease (PAD) results from systemic atherosclerosis, causing narrowing of arteries in the limbs, leading to tissue ischemia, gangrene, and eventually limb amputation. e presence of diabetes greatly increases the risk of PAD, accounting for the majority of lower limb amputations [1]
Patients with diabetes are much more likely to be a ected by small vessel rather than large vessel obstruction leaving them with few treatment options. e use of proangiogenic therapeutics to induce the Contrast Media & Molecular Imaging growth of blood vessels in ischemic tissues of diabetic patients has been intensively studied as an adjunct to endovascular revascularisation, but accurate measurement of the proangiogenic effect is stymied by a lack of sensitive measurement techniques
Small animal positron emission tomography (PET) imaging was performed on days 1, 3, 8, 14, 21, and 28 days postinitiation of hind limb ischemia
Summary
Peripheral artery disease (PAD) results from systemic atherosclerosis, causing narrowing of arteries in the limbs, leading to tissue ischemia, gangrene, and eventually limb amputation. e presence of diabetes greatly increases the risk of PAD, accounting for the majority of lower limb amputations [1]. E use of proangiogenic therapeutics to induce the Contrast Media & Molecular Imaging growth of blood vessels in ischemic tissues of diabetic patients has been intensively studied as an adjunct to endovascular revascularisation, but accurate measurement of the proangiogenic effect is stymied by a lack of sensitive measurement techniques. New blood vessels have been shown to express high levels of integrins. Ese integrins act as receptors for proteins expressing the arginine-glycine-aspartate (RGD) tripeptide motif [5]. Imaging techniques such as positron emission tomography (PET) with RGD peptide radiopharmaceuticals that target integrins have been shown to be a sensitive measure of new blood vessel growth preclinically [6, 7]
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