title: Simvastatin augments revascularization and reperfusion in a murine model of hind limb ischemia - Multimodal imaging assessment.
abstract: BACKGROUND
  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 using99mTc-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 increased99mTc-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 using99mTc-RGD SPECT, which displays significant increases in retention before macrovascular volume changes are measureable with MRI.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A* Star), 11 Biopolis Way, #07-10, Helios, Singapore, 138667; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456. Electronic address: julian_goggi@sbic.a-star.edu.sg.
authors.forename: Julian Luke
authors.initials: JL
authors.lastname: Goggi
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A* Star), 11 Biopolis Way, #07-10, Helios, Singapore, 138667.
authors.forename: Michael
authors.initials: M
authors.lastname: Ng
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A* Star), 11 Biopolis Way, #07-10, Helios, Singapore, 138667.
authors.forename: Nalini
authors.initials: N
authors.lastname: Shenoy
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A* Star), 11 Biopolis Way, #07-10, Helios, Singapore, 138667.
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Boominathan
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A* Star), 11 Biopolis Way, #07-10, Helios, Singapore, 138667.
authors.forename: Peter
authors.initials: P
authors.lastname: Cheng
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A* Star), 11 Biopolis Way, #07-10, Helios, Singapore, 138667.
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Sekar
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A* Star), 11 Biopolis Way, #07-10, Helios, Singapore, 138667.
authors.forename: Kishore Kumar
authors.initials: KK
authors.lastname: Bhakoo
mesh_terms: D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D064847:Multimodal Imaging; D009132:Muscles / Q000098:blood supply / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009842:Oligopeptides / Q000737:chemistry; D012039:Regional Blood Flow / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D013667:Technetium / Q000737:chemistry; D015899:Tomography, Emission-Computed, Single-Photon; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D009842:Oligopeptides; D042461:Vascular Endothelial Growth Factor A; D013667:Technetium; C047981:arginyl-glycyl-aspartic acid; D019821:Simvastatin
keywords: Integrin; Ischemia; MRI; Neovascularization; RGD; Statins