Nitric oxide (NO) is of crucial importance for smooth muscle cell (SMC) function and exerts numerous, sometimes opposing, effects on vascular proliferative diseases. Among these disorders is restenosis, the narrowing of an artery after intra-arterial intervention, such as balloon angioplasty or stent placement. The molecular downstream effectors of NO in restenosis are not clear. In SMCs, NO exerts many of its effects via the second messenger cyclic guanosine-3´,5´-monophosphate (cGMP). The cGMP-dependent protein kinase type I (cGKI) is presumably the major mediator of NO-cGMP signaling in SMCs. The purpose of this study was to examine the functional role of the SMC NO-cGMP-cGKI pathway in restenosis. By using the Cre-loxP site-specific recombination system, tissue-specific mouse mutants were generated in which the cGKI protein was efficiently ablated in SMCs and, to a lesser extent, also in cardiomyocytes. It was tested whether this conditional inactivation of cGKI would effect vascular remodeling after carotid ligation. Remodeling was analyzed by morphometry and immunohistochemistry. Based on the neointima/media ratio and other vessel parameters as well as on various immunostainings, no significant differences were detected between the conditional cGKI mutants and controls at different time points after injury, in normolipidemic as well as in apolipoprotein E-deficient mice. Moreover, continuous treatment of injured wild-type mice with the phosphodiesterase 5 inhibitor sildenafil (Viagra) indicated that elevated cGMP levels had no influence on ligation-induced remodeling. Thus, vascular remodeling after mechanical injury was altered neither by the deletion of smooth muscle cGKI nor by sildenafil treatment. Finally, this work addressed the effects of different cGMP-elevating agents, such as sildenafil, 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA-NO), and natriuretic peptides, on cyclic nucleotide signaling in primary vascular SMCs. These experiments indicated that endogenously generated cGMP might cross-activate cAMP-dependent protein kinase (cAK), at least in the absence of cGKI. Together, the results of the present study indicate that NO signaling in restenosis is independent of the cGMP-cGKI pathway and perhaps mediated via an unconventional NO-cGMP-cAK pathway.     «

Nitric oxide (NO) is of crucial importance for smooth muscle cell (SMC) function and exerts numerous, sometimes opposing, effects on vascular proliferative diseases. Among these disorders is restenosis, the narrowing of an artery after intra-arterial intervention, such as balloon angioplasty or stent placement. The molecular downstream effectors of NO in restenosis are not clear. In SMCs, NO exerts many of its effects via the second messenger cyclic guanosine-3´,5´-monophosphate (cGMP). The cGMP...     »

Die Arbeit untersuchte die in vivo Bedeutung der cGMP-abhängigen Proteinkinase I (cGKI) bei der Gefäßrestenose. Die cGKI ist eine Effektorkinase von Stickstoffmonoxid (NO) und wird über die NO–induzierte Bildung des sekundären Botenstoffs cGMP aktiviert. Für die in vivo Analyse der Restenose wurden transgene Mäuse mit einer selektiven Inaktivierung des cGKI-Gens im glatten Gefäßmuskel und Herzmuskel mittels des Cre/loxP-Rekombinationssystems generiert und einer Gefäßverletzung durch Carotisligatur unterzogen. Weder diese genetische Inaktivierung noch eine Pharmakotherapie der Tiere mit dem cGMP-erhöhenden Phosphodiesterase-5 Inhibitor Sildenafil (Viagra) hatten einen Einfluss auf die Gefäßveränderungen nach der Ligatur. Insgesamt stützen die Ergebnisse dieser Arbeit die Hypothese, dass die Effekte von NO bei der Ligatur-induzierten Restenose nicht durch den cGMP-cGKI Signalweg vermittelt werden.     «

Die Arbeit untersuchte die in vivo Bedeutung der cGMP-abhängigen Proteinkinase I (cGKI) bei der Gefäßrestenose. Die cGKI ist eine Effektorkinase von Stickstoffmonoxid (NO) und wird über die NO–induzierte Bildung des sekundären Botenstoffs cGMP aktiviert. Für die in vivo Analyse der Restenose wurden transgene Mäuse mit einer selektiven Inaktivierung des cGKI-Gens im glatten Gefäßmuskel und Herzmuskel mittels des Cre/loxP-Rekombinationssystems generiert und einer Gefäßverletzung durch Carotisligat...     »