TY  - JOUR
A1  - Schäfer, Andreas
A1  - Burkhardt, Mick
A1  - Vollkommer, Tobias
A1  - Bauersachs, Johann
A1  - Münzel, Thomas
A1  - Walter, Ulrich
A1  - Smolenski, Albert
T1  - Endothelium-dependent and -independent relaxation and VASP serines 157/239 phosphorylation by cyclic nucleotide-elevating vasodilators in rat aorta
T2  - Biochemical pharmacology
N2  - 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 β-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 Ser157 and Ser239. As expected, the effects of acetylcholine were endothelium-dependent. However, relaxation induced by the β-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 Ser239 and Ser157 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.
KW  - Endothelium
KW  - cGMP
KW  - cAMP
KW  - Proteinkinase
KW  - VASP
KW  - Isoproterenol
Y1  - 2014
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/34570
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-345702
SN  - 0006-2952
SN  - 1873-2968
N1  - This item is available under the Attribution-NonCommercial-NoDerivs 3.0 Ireland. No item may be reproduced for commercial purposes. For other possible restrictions on use please refer to the publisher's URL where this is made available, or to notes contained in the item itself. Other terms may apply.
N1  - This is the author’s version of a work that was accepted for publication in Biochemical Pharmacology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Biochemical Pharmacology (VOL 65, ISSUE 3, (2003)) DOI: 10.1016/S0006-2952(02)01523-X
VL  - 65
IS  - 3
SP  - 397
EP  - 405
PB  - Elsevier
CY  - New York, NY
ER  -