Abstract
BackgroundNew therapies to treat diabetic peripheral artery disease (PAD) require target-specific non-invasive imaging modalities to follow efficacy. As a translational study, we performed targeted imaging of receptors for vascular endothelial growth factor (VEGF) in response to anterior femoral artery occlusion (FAO) in Yucatan minipigs and compare the normal response to response in diabetic Yucatan minipigs.MethodsEleven Yucatan minipigs, 6 non-diabetic (non-D) and 5 purpose bred diabetic (D) (Sinclair, Auxvasse MO), underwent intravascular total occlusion of the anterior femoral artery (FA). At days 1 and 28, pigs underwent SPECT/CT 201Tl hindlimb perfusion imaging and at day 7 were injected with [99mTc]DOTA-PEG-scVEGF (scV/Tc) tracer targeting VEGF receptor, and underwent biopsies of the hindlimb muscles for gamma counting and histology, followed by imaging. One day after the final scan, pigs underwent contrast angiography of the lower extremities. Counts from scans were converted to percentage injected activity (%IA).ResultsPerfusion was lower in the occluded hindlimb compared to non-occluded on day 1 in both the D and non-D pigs. At day 7, scV/Tc count ratio of counts from ROIs drawn in proximal gastrocnemius muscle for the occluded over non-occluded limb was significantly higher in non-D vs. D pigs (1.32 ± 0.06 vs. 1.04 ± 0.13, P = 0.02) reflecting higher level of angiogenesis. Perfusion increased between days 1 and 28 in the muscles in the occluded limb for the non-diabetic pigs while the diabetic pig showed no increase (+ 0.13 ± 0.08 %IA vs. − 0.13 ± 0.11, P = 0.003). The anterior FA showed poor contrast filling beyond occluder and qualitatively fewer bridging collaterals compared to non-D pigs at 28 days.ConclusionVEGF receptor targeted imaging showed the effects of diabetes to suppress angiogenesis in response to occlusion of the anterior femoral artery of purpose bred diabetic Yucatan minipigs and indicates potential applicability as a marker to follow efficacy of novel therapies to improve blood flow by stimulating angiogenesis in diabetic PAD.
Highlights
The worldwide incidence of peripheral artery disease (PAD) is high and rising [1, 2]
The Sinclair diabetic Yucatan minipigs have type I diabetes induced with alloxan and are sent to investigators when diabetes is established and the blood sugar stabilized in range of 300–500 mg/dL on 7–8 units NPH Humulin N
The radiotracer we used to image angiogenesis, [99mTc]Dodecane tetra acetic acid (DOTA)-Polyethylene glycol (PEG)-scVEGF, is based on an engineered single-chain recombinant version of VEGF121, site- derivatized with PEGylated chelator DOTA for radiolabeling with 99mTc (14,15). scV/Tc and its receptor-selective versions show nanomolar affinity to VEGFR-1 and VEGFR-2 is readily internalized upon binding to the vascular endothelial growth factor (VEGF) receptors, and it reliably detects VEGF receptor expression in murine models of atherosclerosis and angiogenesis [16, 27]
Summary
The worldwide incidence of peripheral artery disease (PAD) is high and rising [1, 2]. For a 1% increase in HbA1c, the incidence of symptomatic PAD increases by 26% [3]. Current management guidelines include control of risk factors, anticoagulation, statins, and a few drugs such as cilostazol [4, 5]. Despite these management and treatment strategies, many patients have disease progression and require revascularization with limited success [6]. New therapies to treat diabetic peripheral artery disease (PAD) require target-specific non-invasive imaging modalities to follow efficacy. We performed targeted imaging of receptors for vascular endothelial growth factor (VEGF) in response to anterior femoral artery occlusion (FAO) in Yucatan minipigs and compare the normal response to response in diabetic Yucatan minipigs
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