Original ArticleFenofibrate Enhances Neovascularization in a Murine Ischemic Hindlimb ModelKatayama, Akira BSc*; Yamamoto, Yasutaka MD*; Tanaka, Kohei BSc*; Matsubara, Koichi MD†; Sugitani, Miyoko BSc*; Fujihara, Satomi*; Harada, Shingo MD‡; Kaetsu, Yasuhiro MD†; Yoshida, Akio MD*; Hisatome, Ichiro MD*Author Information From the *Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science, Yonago, Japan; †Department of Multidisciplinary Internal Medicine and ‡Division of Organ Regeneration Surgery, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Japan. Received for publication February 20, 2009; accepted June 23, 2009. The authors report no conflicts of interest. Reprints: Yasutaka Yamamoto, MD, Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science, 36-1 Nishi-machi, Yonago 683-8504, Japan (e-mail: firstname.lastname@example.org). Journal of Cardiovascular Pharmacology: November 2009 - Volume 54 - Issue 5 - p 399-404 doi: 10.1097/FJC.0b013e3181bad05d Buy Metrics Abstract Fenofibrate have been illustrated to stimulate nitric oxide (NO) pathway, which plays pivotal roles in neovascularization. Here, we evaluated the effect of fenofibrate on neovascularization using a murine ischemic hindlimb model. C57BL/6J mice were treated with fenofibrate and/or NG-nitro-l-arginine methyl ester hydrochloride (l-NAME) for 28 days after ischemia operation. We exploited a concentration of L-NAME that did not affect blood pressure levels but suppress NO activity. Limb blood perfusion and capillary density in ischemic limb, serum NO levels, and aortic NOS activity were significantly increased by fenofibrate treatment when compared with the untreatment group. And, these effects were abolished by coadministration of L-NAME. Fenofibrate treatment significantly lowered serum triglyceride levels. Cotreatment of L-NAME did not inhibit serum triglyceride level, lowering effect of fenofibrate. These results suggested that the lowering in serum triglyceride levels is not involved in the improvement of neovascularization. In an in vitro experiment, fenofibrate stimulated NOS activity in human umbilical vein endothelial cells. Also, fenofibrate stimulated in vitro angiogenesis, and this effect was abolished by coincubation with L-NAME. In conclusions, fenofibrate enhanced neovascularization in a murine hindlimb ischemia model. The mechanism is most likely through activation of NO pathway in endothelial cells. © 2009 Lippincott Williams & Wilkins, Inc.