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The Effects of Bilirubin on Angiogenesis in Mice with Hindlimb Ischemia
Author(s) -
Ikeda Yasumasa,
Kanai Yusuke,
Horinouchi Yuya,
IzawaIshizawa Yuki,
Kihira Yoshitaka,
Miyamoto Licht,
Ishizawa Keisuke,
Tsuchiya Koichiro,
Tamaki Toshiaki
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.639.1
Subject(s) - bilirubin , angiogenesis , protein kinase b , enos , endocrinology , medicine , hindlimb , endothelial stem cell , vasodilation , nitric oxide , chemistry , pharmacology , phosphorylation , biochemistry , nitric oxide synthase , in vitro
Background Low serum bilirubin levels are associated with peripheral artery disease. Bilirubin is known to exert anti‐oxidant effect and the enhancement of flow‐mediated vasodilation, however, bilirubin action on angiogenesis remains unclear. In this study, we examine the mechanism of bilirubin on angiogenic effect. Methods and Results We employed C57BL/6J mice with unilateral hindlimb ischemia surgery and divided the mice into two groups (vehicle‐treated group and bilirubin treated group). The analysis of laser speckle blood flow demonstrated that the recovery of blood flow in response to ischemic hindlimb was promoted in mice with bilirubin treatment. The capillary density was significantly higher in ischemic lower limb of bilirubin‐treated mice. The phosphorylated levels of endothelial nitric oxide synthesis (eNOS) and Akt were augmented in ischemic tissues of mice with bilirubin treatment compared vehicle treatment. In in vitro experiments by using human aortic endothelial cells, bilirubin increased eNOS and Akt phosphorylation. Bilirubin also augmented cell proliferation, cell migration and tube formation. These bilirubin action on endothelial cell activation were abolished by LY294002, a phosphatidylinositol 3‐kinase inhibitor. Conclusion Bilirubin promotes angiogenesis through endothelial cells activation via Akt‐eNOS‐dependent axis.