title: Androgen receptor promotes sex-independent angiogenesis in response to ischemia and is required for activation of vascular endothelial growth factor receptor signaling.
abstract: BACKGROUND
  Hypoandrogenemia is associated with an increased risk of ischemic diseases. Because actions of androgens are exerted through androgen receptor (AR) activation, we studied hind-limb ischemia in AR knockout mice to elucidate the role of AR in response to ischemia.
  
  
  RESULTS
  Both male and female AR knockout mice exhibited impaired blood flow recovery, more cellular apoptosis, and a higher incidence of autoamputation after ischemia. In ex vivo and in vivo angiogenesis studies, AR-deficient vascular endothelial cells showed reduced angiogenic capability. In ischemic limbs of AR knockout mice, reductions in the phosphorylation of the Akt protein kinase and endothelial nitric oxide synthase were observed despite a robust increase in hypoxia-inducible factor 1α and vascular endothelial cell growth factor (VEGF) gene expression. In in vitro studies, siRNA-mediated ablation of AR in vascular endothelial cells blunted VEGF-stimulated phosphorylation of Akt and endothelial nitric oxide synthase. Immunoprecipitation experiments documented an association between AR and kinase insert domain protein receptor that promoted the recruitment of downstream signaling components.
  
  
  CONCLUSIONS
  These results document a physiological role of AR in sex-independent angiogenic potency and provide evidence of novel cross-talk between the androgen/AR signaling and VEGF/kinase insert domain protein receptor signaling pathways.
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Health Biosciences, 3-18-15 Kuramoto-cho Tokushima 770-8503, Japan. toshio.matsumoto@tokushima-u.ac.jp
authors.forename: Sumiko
authors.initials: S
authors.lastname: Yoshida
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Aihara
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sumitomo-Ueda
authors.forename: Ryoko
authors.initials: R
authors.lastname: Uemoto
authors.forename: Kazue
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ise
authors.forename: Shusuke
authors.initials: S
authors.lastname: Yagi
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwase
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Mouri
authors.forename: Matomo
authors.initials: M
authors.lastname: Sakari
authors.forename: Takahiro
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Takeyama
authors.forename: Masashi
authors.initials: M
authors.lastname: Akaike
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D000672:Amputation Stumps / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002196:Capillaries / Q000502:physiology; D005260:Female; D005262:Feminization / Q000235:genetics / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007511:Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000502:physiology; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D011944:Receptors, Androgen; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; D016392:Proto-Oncogene Proteins pp60(c-src); C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt1 protein, mouse; angiogenesis inducing agents; nitric oxide synthase type III; receptors, androgen; vascular endothelial growth factor receptor-2