Central role of calcium-dependent tyrosine kinase PYK2 in endothelial nitric oxide synthase : Mediated angiogenic response and vascular function

The involvement of Ca2+-dependent tyrosine kinase PYK2 in the Akt/endothelial NO synthase pathway remains to be determined. Blood flow recovery and neovessel formation after hind-limb ischemia were impaired in PYK2-/- mice with reduced mobilization of endothelial progenitors. Vascular endothelial gr...

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Published in:Circulation (New York, N.Y.) N.Y.), 2007-08, Vol.116 (9), p.1041-1051
Main Authors: MATSUI, Akihiro, OKIGAKI, Mitsuhiko, TATEISHI, Kento, MATSUNAGA, Shinsaku, KATSUME, Asako, HONSHOU, Shoken, TAKAHASHI, Tomosaburo, MATOBA, Satoaki, KUSABA, Tetsuro, TATSUMI, Tetsuya, MATSUBARA, Hiroaki, AMANO, Katsuya, ADACHI, Yasushi, DENAN JIN, TAKAI, Shinji, YAMASHITA, Tomoya, KAWASHIMA, Seinosuke, KURIHARA, Tatsuya, MIYAZAKI, Mizuo
Format: Article
Language:English
Subjects:
Analysis of Variance
Animals
Atherosclerosis (general aspects, experimental research)
Biological and medical sciences
Blood and lymphatic vessels
Calcium - physiology
Cardiology. Vascular system
Coronary heart disease
Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous
Enzyme Activation
Focal Adhesion Kinase 2 - deficiency
Focal Adhesion Kinase 2 - physiology
Heart
Heart - physiology
Hindlimb - blood supply
Ischemia - physiopathology
Medical sciences
Mice
Mice, Knockout
Neovascularization, Physiologic - physiology
Nitric Oxide Synthase Type III - metabolism
Oncogene Protein v-akt - physiology
Phosphorylation
Signal Transduction
Vascular Endothelial Growth Factor A - physiology
Vasodilation
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Summary:The involvement of Ca2+-dependent tyrosine kinase PYK2 in the Akt/endothelial NO synthase pathway remains to be determined. 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. 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.
ISSN:0009-7322
1524-4539
DOI:10.1161/circulationaha.106.645416