title: Role of smooth muscle cGMP/cGKI signaling in murine vascular restenosis.
abstract: 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.
authors.affiliation: Institut für Pharmakologie und Toxikologie der TUM, Biedersteiner Str. 29, D-80802 München, Germany. lukowski@ipt.med.tu-muenchen.de
authors.forename: Robert
authors.initials: R
authors.lastname: Lukowski
authors.forename: Pascal
authors.initials: P
authors.lastname: Weinmeister
authors.forename: Dominik
authors.initials: D
authors.lastname: Bernhard
authors.forename: Susanne
authors.initials: S
authors.lastname: Feil
authors.forename: Michael
authors.initials: M
authors.lastname: Gotthardt
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.forename: Steffen
authors.initials: S
authors.lastname: Massberg
authors.forename: Alma
authors.initials: A
authors.lastname: Zernecke
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: Franz
authors.initials: F
authors.lastname: Hofmann
authors.forename: Robert
authors.initials: R
authors.lastname: Feil
mesh_terms: 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
chemical_list: 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