title: Smooth muscle-specific deletion of nitric oxide-sensitive guanylyl cyclase is sufficient to induce hypertension in mice.
abstract: BACKGROUND
  Arterial hypertension is one of the major diseases in industrial countries and a major cause of mortality. One of the main vascular factors responsible for the relaxation of blood vessels and regulation of blood pressure is nitric oxide (NO). NO acts predominantly via NO-sensitive guanylyl cyclase (NO-GC), which is made up of 2 different subunits (alpha and beta). Deletion of the beta(1) subunit leads to a global NO-GC knockout, and these mice are hypertensive. However, global deletion of NO-GC in mice does not allow identification of the cell/tissue type responsible for the elevated blood pressure.
  
  
  RESULTS
  To determine the relative contribution of smooth muscle cells to the hypertension seen in NO-GC knockout mice, we generated smooth muscle-specific knockout mice for the beta(1) subunit of NO-GC using a tamoxifen-inducible system. Male mice were investigated because the Cre transgene used is located on the Y chromosome. Tamoxifen injection led to a rapid reduction of NO-GC expression in smooth muscle but did not affect that in other tissues. Parallel to a reduction in NO-induced cGMP accumulation, NO-induced relaxation of aortic smooth muscle was gradually lost after induction by tamoxifen. Concomitantly, these animals developed hypertension within 3 to 4 weeks.
  
  
  CONCLUSIONS
  We generated a model in which the development of hypertension can be visualized over time by deletion of a single gene in smooth muscle cells. In sum, our data provide evidence that deletion of NO-GC solely in smooth muscle is sufficient to cause hypertension.
authors.affiliation: Physiologisches Institut I, Universität Würzburg, Würzburg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Groneberg
authors.forename: Peter
authors.initials: P
authors.lastname: König
authors.forename: Angela
authors.initials: A
authors.lastname: Wirth
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Doris
authors.initials: D
authors.lastname: Koesling
authors.forename: Andreas
authors.initials: A
authors.lastname: Friebe
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000201:enzymology; D001794:Blood Pressure / Q000502:physiology; D001921:Brain / Q000201:enzymology; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D045462:Endothelium-Dependent Relaxing Factors / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006162:Guanylate Cyclase / Q000235:genetics* / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism*; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism*; D000068677:Sildenafil Citrate; D000071756:Soluble Guanylyl Cyclase; D013450:Sulfones / Q000494:pharmacology; D013629:Tamoxifen; D019076:Transgenes / Q000235:genetics; D014664:Vasodilation / Q000502:physiology
chemical_list: D045462:Endothelium-Dependent Relaxing Factors; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D021122:Protein Subunits; D011687:Purines; D018160:Receptors, Cytoplasmic and Nuclear; D013450:Sulfones; D013629:Tamoxifen; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP