Metformin stimulates ischemia-induced revascularization through an eNOS dependent pathway in the ischemic hindlimb mice model Noriko Takahashi, MD, Rei.

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Metformin stimulates ischemia-induced revascularization through an eNOS dependent pathway in the ischemic hindlimb mice model Noriko Takahashi, MD, Rei Shibata, MD, PhD, Noriyuki Ouchi, MD, PhD, Masayuki Sugimoto, MD, PhD, Toyoaki Murohara, MD, PhD, Kimihiro Komori, MD, PhD Journal of Vascular Surgery Volume 61, Issue 2, Pages 489-496 (February 2015) DOI: 10.1016/j.jvs.2013.09.061 Copyright © 2015 Society for Vascular Surgery Terms and Conditions

Fig 1 Metformin improves perfusion of ischemic limbs in wild-type (WT) mice. A, Representative images of laser Doppler blood flowmetry (LDBF) for WT mice treated with or without metformin before surgery and at different time points after surgery. Low perfusion signals (dark blue) were observed in the ischemic hindlimb of WT mice, whereas high perfusion signals (white to red) were detected in WT mice treated with metformin on postoperative day 3, 7, 14, 21, and 28. B, Quantitative analysis of ischemic/normal LDBF ratio in WT mice (n = 10 in each group) treated with or without metformin (*P < .05 vs control). Journal of Vascular Surgery 2015 61, 489-496DOI: (10.1016/j.jvs.2013.09.061) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

Fig 2 Increased capillary and arteriole density in ischemic metformin-treated wild-type (WT) mice. A, Immunostaining of ischemic tissues with anti-CD31 monoclonal antibody (green) on postoperative day 28 (×400). B, Quantitative analysis of capillary density in WT (n = 10 in each group) treated with or without metformin (300 mg/kg/d). C, Immunostaining of ischemic tissues with anti-α-smooth muscle actin antibody (red) on postoperative day 28 (×400). D, Quantitative analysis of arteriole density in WT (n = 10 in each group) treated with or without metformin (300 mg/kg/d). Journal of Vascular Surgery 2015 61, 489-496DOI: (10.1016/j.jvs.2013.09.061) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

Fig 3 Effect of metformin on phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS) in ischemic muscle in wild-type (WT) mice. Western immunoblots with the indicated antibodies were performed on the ischemic adductor muscle of WT mice treated with or without metformin (300 mg/kg/d) at 7 days after surgery. A, The representative immunoblots and B, quantitative analysis of relative changes in total and phosphorylated AMPK and eNOS. AMPK and eNOS were normalized to α-tubulin signal and expressed as percentage of the signal intensity of untreated WT mice (n = 10). Journal of Vascular Surgery 2015 61, 489-496DOI: (10.1016/j.jvs.2013.09.061) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

Fig 4 Adenosine monophosphate-activated protein kinase (AMPK)/endothelial nitric oxide synthase (eNOS) pathway is required for metformin-induced revascularization. A, Quantitative analysis of ischemic/normal laser Doppler blood flowmetry (LDBF) ratio in eNOS deficient (eNOS-KO) mice (n = 5 in each group) treated with or without metformin (300 mg/kg/d). B, Clinical score in eNOS-KO mice treated with or without metformin (300 mg/kg/d) as determined by an index of severity of limb ischemia. C, Quantitative analysis of capillary density in eNOS-KO mice (n = 5 in each group) treated with or without metformin (300 mg/kg/d). D, Quantitative analysis of arteriole density in eNOS-KO mice (n = 5 in each group) treated with or without metformin (300 mg/kg/d). E, The representative immunoblots and quantitative analysis of relative changes in phosphorylated AMPK in eNOS-KO mice treated with or without metformin at 7 days after surgery. Western immunoblots with the indicated antibodies were performed on the ischemic adductor muscle of eNOS-KO mice treated with or without metformin at 7 days after surgery. Phosphorylation of AMPK was normalized to α-tubulin signal and expressed as a percentage of the signal intensity of untreated eNOS-KO mice (n = 5). Journal of Vascular Surgery 2015 61, 489-496DOI: (10.1016/j.jvs.2013.09.061) Copyright © 2015 Society for Vascular Surgery Terms and Conditions