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首页> 外文期刊>Biochemical Pharmacology >Endothelium-dependent and -independent relaxation and VASP serines 157/239 phosphorylation by cyclic nucleotide-elevating vasodilators in rat aorta.
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Endothelium-dependent and -independent relaxation and VASP serines 157/239 phosphorylation by cyclic nucleotide-elevating vasodilators in rat aorta.

机译：内皮依赖性和非依赖性松弛和VASP丝氨酸157/239磷酸化的大鼠主动脉中环核苷酸升高的血管舒张剂。

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Endothelium-dependent vasodilation is thought to be mediated primarily by the NO/cGMP signaling pathway whereas cAMP-elevating vasodilators are considered to act independent of the endothelial cell layer. However, recent functional data suggest that cAMP-elevating vasodilators such as beta-receptor agonists, adenosine or forskolin may also be endothelium-dependent. Here we used functional and biochemical assays to analyze endothelium-dependent, cGMP- and cAMP-mediated signaling in rat aorta. Acetylcholine and sodium nitroprusside (SNP) induced a concentration-dependent relaxation of phenylephrine-precontracted aorta. This response was reflected by the phosphorylation of the vasodilator-stimulated phosphoprotein (VASP), a validated substrate of cGMP- and cAMP-dependent protein kinases (cGK, cAK), on Ser(157) and Ser(239). As expected, the effects of acetylcholine were endothelium-dependent. However, relaxation induced by the beta-receptor agonist isoproterenol was also almost completely impaired after endothelial denudation. At the biochemical level, acetylcholine- and isoproterenol-evoked cGK and cAK activation, respectively, as measured by VASP Ser(239) and Ser(157) phosphorylation, was strongly diminished. Furthermore, the effects of isoproterenol were repressed by eNOS inhibition when endothelium was present. We also observed that the relaxing and biochemical effects of forskolin were at least partially endothelium-dependent. We conclude that cAMP-elevating vasodilators, i.e. isoproterenol and to a lesser extent also forskolin, induce vasodilation and concomitant cyclic nucleotide protein kinase activation in the vessel wall in an endothelium-dependent way.
机译：内皮依赖性血管舒张被认为主要由NO / cGMP信号传导途径介导，而cAMP升高的血管舒张剂被认为独立于内皮细胞层起作用。但是，最近的功能数据表明，cAMP升高的血管扩张剂（例如β受体激动剂，腺苷或毛喉素）也可能是内皮依赖性的。在这里，我们使用功能和生化分析来分析大鼠主动脉中的内皮依赖性，cGMP和cAMP介导的信号传导。乙酰胆碱和硝普钠（SNP）诱导了苯肾上腺素预收缩主动脉的浓度依赖性舒张。此反应通过血管舒张剂刺激的磷蛋白（VASP）的磷酸化反映出来，VASP是一种经验证的cGMP和cAMP依赖性蛋白激酶（cGK，cAK）的底物，位于Ser（157）和Ser（239）上。如所预期的，乙酰胆碱的作用是内皮依赖性的。然而，在内皮剥脱后，β-受体激动剂异丙肾上腺素引起的松弛也几乎完全受损。在生化水平上，分别通过VASP Ser（239）和Ser（157）磷酸化测量的乙酰胆碱和异丙肾上腺素引起的cGK和cAK活化大大降低。此外，当存在内皮时，eNOS抑制可抑制异丙肾上腺素的作用。我们还观察到，佛司可林的松弛和生化作用至少部分依赖于内皮。我们得出的结论是，cAMP升高的血管扩张剂，即异丙肾上腺素和较小程度的福司可林，以血管内皮依赖性方式诱导血管壁的血管扩张和伴随的环状核苷酸蛋白激酶活化。

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