title: Central role of calcium-dependent tyrosine kinase PYK2 in endothelial nitric oxide synthase-mediated angiogenic response and vascular function.
abstract: BACKGROUND
  The involvement of Ca2+-dependent tyrosine kinase PYK2 in the Akt/endothelial NO synthase pathway remains to be determined.
  
  
  RESULTS
  Blood flow recovery and neovessel formation after hind-limb ischemia were impaired in PYK2-/- mice with reduced mobilization of endothelial progenitors. Vascular endothelial growth factor (VEGF)-mediated cytoplasmic Ca2+ mobilization and Ca2+-independent Akt activation were markedly decreased in the PYK2-deficient aortic endothelial cells, whereas the Ca2+-independent AMP-activated protein kinase/protein kinase-A pathway that phosphorylates endothelial NO synthase was not impaired. Acetylcholine-mediated aortic vasorelaxation and cGMP production were significantly decreased. Vascular endothelial growth factor-dependent migration, tube formation, and actin cytoskeletal reorganization associated with Rac1 activation were inhibited in PYK2-deficient endothelial cells. PI3-kinase is associated with vascular endothelial growth factor-induced PYK2/Src complex, and inhibition of Src blocked Akt activation. The vascular endothelial growth factor-mediated Src association with PLCgamma1 and phosphorylation of 783Tyr-PLCgamma1 also were abolished by PYK2 deficiency.
  
  
  CONCLUSIONS
  These findings demonstrate that PYK2 is closely involved in receptor- or ischemia-activated signaling events via Src/PLCgamma1 and Src/PI3-kinase/Akt pathways, leading to endothelial NO synthase phosphorylation, and thus modulates endothelial NO synthase-mediated vasoactive function and angiogenic response.
authors: Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, 602-8566, Japan.
authors: Akihiro
authors: A
authors: Matsui
authors: Mitsuhiko
authors: M
authors: Okigaki
authors: Katsuya
authors: K
authors: Amano
authors: Yasushi
authors: Y
authors: Adachi
authors: Denan
authors: D
authors: Jin
authors: Shinji
authors: S
authors: Takai
authors: Tomoya
authors: T
authors: Yamashita
authors: Seinosuke
authors: S
authors: Kawashima
authors: Tatsuya
authors: T
authors: Kurihara
authors: Mizuo
authors: M
authors: Miyazaki
authors: Kento
authors: K
authors: Tateishi
authors: Shinsaku
authors: S
authors: Matsunaga
authors: Asako
authors: A
authors: Katsume
authors: Shoken
authors: S
authors: Honshou
authors: Tomosaburo
authors: T
authors: Takahashi
authors: Satoaki
authors: S
authors: Matoba
authors: Tetsuro
authors: T
authors: Kusaba
authors: Tetsuya
authors: T
authors: Tatsumi
authors: Hiroaki
authors: H
authors: Matsubara
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000502:physiology; D004789:Enzyme Activation; D051418:Focal Adhesion Kinase 2 / Q000172:deficiency / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000502:physiology*; D010766:Phosphorylation; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D014664:Vasodilation
chemical_list: D042461:Vascular Endothelial Growth Factor A; D052250:Nitric Oxide Synthase Type III; D051418:Focal Adhesion Kinase 2; D051058:Oncogene Protein v-akt; D002118:Calcium