Nanoparticle-mediated endothelial cell-selective delivery of pitavastatin induces functional collateral arteries (therapeutic arteriogenesis) in a rabbit.

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Nanoparticle-mediated endothelial cell-selective delivery of pitavastatin induces functional collateral arteries (therapeutic arteriogenesis) in a rabbit model of chronic hind limb ischemia Shinichiro Oda, MD, Ryoji Nagahama, MSc, Kaku Nakano, PhD, Tetsuya Matoba, MD, Mitsuki Kubo, MD, PhD, Kenji Sunagawa, MD, PhD, Ryuji Tominaga, MD, PhD, Kensuke Egashira, MD, PhD Journal of Vascular Surgery Volume 52, Issue 2, Pages 412-420 (August 2010) DOI: 10.1016/j.jvs.2010.03.020 Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 1 Effects of six statins on angiogenic capacity of human endothelial cells in vitro is shown by quantitative analysis of tube formation (tube length in mm per well) in six independent experiments. *P < .01 vs control by one-way analysis of variance with the Dunnett multiple comparison test. Journal of Vascular Surgery 2010 52, 412-420DOI: (10.1016/j.jvs.2010.03.020) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 2 Effects of pitavastatin and pitavastatin nanoparticles (NP) are shown on the angiogenic capacity of human endothelial cells in vitro by quantitative analysis of tube formation (tube length per well) of six independent experiments. *P < .01 vs control by two-way analysis of variance with the Dunnett multiple comparison test. Journal of Vascular Surgery 2010 52, 412-420DOI: (10.1016/j.jvs.2010.03.020) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 3 Effects of pitavastatin nanoparticles (NP) on angiographically visible collateral arterial development are shown 28 days after treatment. A, Effects of pitavastatin-NP containing 0.05, 0.15, or 0.5 mg/kg pitavastatin on the angiographic score (n = 3 each). B, Representative angiograms are shown of the phosphate buffered saline (PBS), pitavastatin-only, fluorescein isothiocyanate (FITC)-NP, and pitavastatin-NP groups at 28 days after treatment. Corkscrew-like collateral arteries were observed only in the pitavastatin-NP group. C, Summary of the angiographic scores obtained for the four groups in panel B (n = 6 each). Journal of Vascular Surgery 2010 52, 412-420DOI: (10.1016/j.jvs.2010.03.020) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 4 Effects of pitavastatin nanoparticles (NP) on angiogenesis and arteriogenesis are shown 28 days after treatment. A, CD-31+ capillary density and capillary/muscle fiber ratio (indices of angiogenesis) is shown in ischemic muscles (n = 6 each). B, α-Smooth muscle actin (α-SMA)-positive arteriolar density and arteriole/muscle fiber ratio is shown in ischemic muscles (indices of arteriogenesis; n = 8 each). FITC, Fluorescein isothiocyanate; PBS, phosphate-buffered saline; SMC, smooth muscle cells. Journal of Vascular Surgery 2010 52, 412-420DOI: (10.1016/j.jvs.2010.03.020) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 5 Cellular distribution of nanoparticles is shown in ischemic muscles. A, Fluorescent photomicrographs show cross sections of control nonischemic muscle and ischemic muscles at 3, 7, and 28 days after fluorescein isothiocyanate (FITC) nanoparticle (NP) injection. Nuclei were counterstained with 4′,6-diamidino-2-phenylindole (blue). Fluorescence microscopic settings (exposure, filter, excitation light intensity, etc.) were the same for all images. Scale bar = 100 μm. B, Photomicrographs of cross sections of ischemic muscle 28 days after FITC-NP injection stained immunohistochemically with the endothelial marker CD31 (red). Most FITC signals colocalized with the vascular endothelium (arrows). Scale bars = 20 μm. Journal of Vascular Surgery 2010 52, 412-420DOI: (10.1016/j.jvs.2010.03.020) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 6 Effects are shown of pitavastatin nanoparticles (NP) on exercise-induced ischemia induced by electrical stimulation. A, Oxygen saturation in the femoral artery and vein in ischemic muscle is shown before and 15 and 30 minutes after muscular exercise by electrical stimulation in the phosphate-buffered saline (PBS) group (n = 6 each). B, The difference in arterial and venous oxygen saturation after 30 minutes of electrical pulse is shown in the four groups (n = 6 each). FITC, Fluorescein isothiocyanate. Journal of Vascular Surgery 2010 52, 412-420DOI: (10.1016/j.jvs.2010.03.020) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 7 Effects of vatalanib nanoparticles (NP) are shown on angiogenesis and arteriogenesis induced by pitavastatin-NP. A, Representative angiograms show vatalanib-NP only and vatalanib-NP plus pitavastatin-NP groups 28 days after treatment. B, Summary of the angiographic scores obtained for the four groups (n = 3 each). C, Effects of vatalanib-NP are shown on histopathologic angiographic (capillary density) and arteriogenic (SMC-positive arteriolar density) responses induced by pitavastatin-NP. Journal of Vascular Surgery 2010 52, 412-420DOI: (10.1016/j.jvs.2010.03.020) Copyright © 2010 Society for Vascular Surgery Terms and Conditions