Central role of calcium-dependent tyrosine kinase PYK2 in endothelial nitric oxide synthase-mediated angiogenic response and vascular function
Central role of calcium-dependent tyrosine kinase PYK2 in endothelial nitric oxide synthase-mediated angiogenic response and vascular function
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DOI：
10.1161/circulationaha.106.645416
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发表时间：
2007-08-28
期刊：
影响因子：
37.8
通讯作者：
Matsubara, Hiroaki
中科院分区：
文献类型：
--
作者：
Matsui, Akihiro;Okigaki, Mitsuhiko;Matsubara, Hiroaki
Background-The involvement of Ca2+-dependent tyrosine kinase PYK2 in the Akt/endothelial NO synthase pathway remains to be determined.Methods and Results-Blood flow recovery and neovesses formation after hindly limb ischemia were impaired in PYK2（-/-）mice with reduced mobilization of endothelial progenitors.血管内皮生长因子（VEGF）介导的胞浆Ca 2+动员和Ca 2+非依赖性Akt激活在PYK 2缺陷的主动脉内皮细胞中显著减少，而Ca 2+非依赖性AMP激活的蛋白激酶/蛋白激酶-A通路磷酸化内皮NO合酶没有受损。乙酰胆碱介导的主动脉血管舒张和cGMP的产生显着减少。血管内皮生长因子依赖的迁移，管形成，肌动蛋白细胞骨架重组与Rac 1激活抑制PYK 2缺陷的内皮细胞。PI 3-激酶与血管内皮生长因子诱导的PYK 2/Src复合物有关，抑制Src可阻断Akt的激活。PYK 2缺陷也可抑制血管内皮生长因子介导的Src与PLC γ 1的结合和（783）Tyr-PLC γ 1的磷酸化。结论这些发现表明PYK 2通过Src/PLC γ 1和Src/PI 3- kinase/Akt途径密切参与受体或缺血激活的信号传导事件，导致内皮NO合成酶磷酸化，从而调节内皮NO-转移酶介导的血管活性功能和血管生成反应。
Background-The involvement of Ca2+-dependent tyrosine kinase PYK2 in the Akt/endothelial NO synthase pathway remains to be determined.Methods and 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 PLC gamma 1 and phosphorylation of (783)Tyr-PLC gamma 1 also were abolished by PYK2 deficiency.Conclusion-These findings demonstrate that PYK2 is closely involved in receptor- or ischemia-activated signaling events via Src/PLC gamma 1 and Src/PI3- kinase/Akt pathways, leading to endothelial NO synthase phosphorylation, and thus modulates endothelial NO synthase-mediated vasoactive function and angiogenic response.