Simvastatin augments revascularization and reperfusion in a murine model of hind limb ischemia - Multimodal imaging assessment.
INTRODUCTION
Peripheral artery disease can lead to severe disability and limb loss. Therapeutic strategies focussing on macrovascular repair have shown benefit but have not significantly reduced amputation rates in progressive PAD. Proangiogenic small molecule therapies may substantially improve vascularisation in limb ischemia. The purpose of the current study was to assess the proangiogenic effects of simvastatin in a murine model of hind limb ischemia using longitudinal multimodal imaging.


METHODS
Mice underwent surgical intervention to induce hind limb ischemia, and were treated with simvastatin orally for 28days. Neovascularisation was assessed using 99mTc-RGD SPECT 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.


RESULTS
Simvastatin significantly increased 99mTc-RGD retention in the ischemic hind limb by day 3 post-surgery, with maximal retention at day 8. Vascular volume was significantly increased in the ischemic hind limb of simvastatin treated animals, but only by day 22. Immunohistochemical analysis shows that simvastatin significantly augmented tissue VEGF expression from day 8 with increase in capillary density (CD31+) from day 14.


CONCLUSIONS
Early assessment of proangiogenic therapy efficacy can be identified using 99mTc-RGD SPECT, which displays significant increases in retention before macrovascular volume changes are measureable with MRI.


ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE
Simvastatin offers an effective proangiogenic therapy as an adjunct for management of limb ischemia. Simvastatin induces integrin expression and vascular remodeling leading to neovascularisation and improved perfusion.
['Goggi|Julian Luke|JL|', 'Ng|Michael|M|', 'Shenoy|Nalini|N|', 'Boominathan|Ramasamy|R|', 'Cheng|Peter|P|', 'Sekar|Sakthivel|S|', 'Bhakoo|Kishore Kumar|KK|']
D000818:Animals D002196:Capillaries D004195:Disease Models, Animal D005786:Gene Expression Regulation D006614:Hindlimb D007511:Ischemia D008279:Magnetic Resonance Imaging D008297:Male D051379:Mice D008807:Mice, Inbred BALB C D064847:Multimodal Imaging D009132:Muscles D018919:Neovascularization, Physiologic D009842:Oligopeptides D012039:Regional Blood Flow D019821:Simvastatin D013667:Technetium D015899:Tomography, Emission-Computed, Single-Photon D042461:Vascular Endothelial Growth Factor A
Ischemia MRI Integrin Neovascularization RGD Statins