VEGF receptor targeted imaging of angiogenic response to limb ischemia in diabetic vs. non-diabetic Yucatan minipigs

Abstract

Background: New 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. Methods: Eleven 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 201 Tl hindlimb perfusion imaging and at day 7 were injected with [ 99m Tc]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). Results: Perfusion 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. Conclusion: VEGF 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.

VEGF‐delivering PEG hydrogels promote vascularization in the porcine subcutaneous space

“…This work aims to establish a baseline model for future studies focused on vascularizing islets delivered to the subcutaneous space of diabetic pigs. Thus, we selected the Yucatan minipig given its extensive use as a preclinical model for diabetes 54–56 and its anatomical similarities in anatomy and vasculature to humans 57 . We chose the ventral subcutaneous space among others (e.g., dorsal) to mimic the standard implant location of continuous glucose monitors 58,59 .…”

Molecular Imaging of Lower Extremity Peripheral Arterial Disease: An Emerging Field in Nuclear Medicine

“…Beyond the various clinical investigations focused on nuclear imaging of PAD, a large number of pre-clinical studies have been published in recent years that also highlight ongoing developments in the field of molecular imaging that could possess translational potential for PAD patients. These studies have utilized large and small animal models of atherosclerosis and hindlimb ischemia to validate novel SPECT-and PET-based approaches directed at perfusion (54) and angiogenesis targeted imaging (55)(56)(57), which continue to be the primary areas of pre-clinical PAD research. Overall, molecular imaging of lower extremity PAD remains a developing and exciting field of research that should provide novel insight into PAD pathophysiology and eventually expand the repertoire of non-invasive tests available to vascular medicine specialists.…”