Role of smooth muscle cGMP/cGKI signaling in murine vascular restenosis.
BACKGROUND
Nitric oxide (NO) is of crucial importance for smooth muscle cell (SMC) function and exerts numerous, and sometimes opposing, effects on vascular restenosis. Although cGMP-dependent protein kinase type I (cGKI) is a principal effector of NO, the molecular pathway of vascular NO signaling in restenosis is unclear. The purpose of this study was to examine the functional role of the smooth muscle cGMP/cGKI signaling cascade in restenosis of vessels.


RESULTS
Tissue-specific mouse mutants were generated in which the cGKI protein was ablated in SMCs. We investigated whether the absence of cGKI in SMCs would affect vascular remodeling after carotid ligation or removal of the endothelium. No differences were detected between the tissue-specific cGKI mutants and control mice at different time points after vascular injury on a normolipidemic or apoE-deficient background. In line with these results, chronic drug treatment of injured control mice with the phosphodiesterase-5 inhibitor sildenafil elevated cGMP levels but had no influence on the ligation-induced remodeling.


CONCLUSIONS
The genetic and pharmacological manipulation of the cGMP/cGKI signaling indicates that this pathway is not involved in the protective effects of NO, suggesting that NO affects vascular remodeling during restenosis via alternative mechanisms.
Lukowski
Robert
R
Institut für Pharmakologie und Toxikologie der TUM, Biedersteiner Str. 29, D-80802 München, Germany. lukowski@ipt.med.tu-muenchen.de
Weinmeister
Pascal
P
Bernhard
Dominik
D
Feil
Susanne
S
Gotthardt
Michael
M
Herz
Joachim
J
Massberg
Steffen
S
Zernecke
Alma
A
Weber
Christian
C
Hofmann
Franz
F
Feil
Robert
R
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D020212:Carotid Artery Injuries / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D017536:Carotid Artery, Common / Q000378:metabolism / Q000601:surgery; D016893:Carotid Stenosis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006152:Cyclic GMP / Q000378:metabolism*; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D004195:Disease Models, Animal; D008026:Ligation; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D013997:Time Factors
D001057:Apolipoproteins E; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569720:Prkg1 protein, mouse; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP