title: Vascular smooth muscle overexpression of G protein-coupled receptor kinase 5 elevates blood pressure, which segregates with sex and is dependent on Gi-mediated signaling.
abstract: BACKGROUND
  Essential hypertension involves an increase in sympathetic nervous system activity and an associated decrease in beta-adrenergic receptor (AR)-mediated dilation. In addition, increased levels of G protein-coupled receptor (GPCR) kinases (GRKs), which regulate GPCR signaling, are associated with increased blood pressure (BP).
  
  
  RESULTS
  We generated transgenic mice with approximately 2-fold vascular smooth muscle (VSM)-specific overexpression of GRK5 to recapitulate a selective aspect of hypertension and understand the impact on GPCR regulation of BP. VSM-GRK5 mice were hypertensive, with a 25% to 35% increase in BP, whereas there was no concomitant cardiac or VSM hypertrophy. BP elevations were segregated with sex, with male mice having higher levels than female mice, and ovariectomy did not alter this phenotype. BP was restored to control values with pertussis toxin Gi-signaling inhibition or chronic beta1AR inhibition after 7 days of CGP20712A, whereas the beta2AR antagonist ICI 118,551 was ineffective. Alpha1AR response was not altered, nor was betaAR-mediated dilation in male blood vessels, whereas norepinephrine sensitivity was increased. In contrast, female VSM-GRK5 blood vessels have diminished betaAR-mediated dilation and enhanced sensitivity to angiotensin II (Ang II).
  
  
  CONCLUSIONS
  Our data suggest that in both male and female mice, VSM-specific overexpression of GRK5 elevates BP mediated by Gi and, at least in part, by beta1AR in males and Ang II receptors in females. Understanding mechanisms underlying an increase in VSM-GRK5 may have a profound influence on the use and development of antihypertensive therapeutics.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC, USA.
authors.forename: Janelle R
authors.initials: JR
authors.lastname: Keys
authors.forename: Rui-Hai
authors.initials: RH
authors.lastname: Zhou
authors.forename: David M
authors.initials: DM
authors.lastname: Harris
authors.forename: Charles A
authors.initials: CA
authors.lastname: Druckman
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Eckhart
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D054774:G-Protein-Coupled Receptor Kinase 5; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D010052:Ovariectomy; D015221:Potassium Channels / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D012727:Sex Characteristics; D015398:Signal Transduction / Q000502:physiology; D019076:Transgenes / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D015221:Potassium Channels; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D011189:Potassium Chloride; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D054774:G-Protein-Coupled Receptor Kinase 5; C517895:Grk5 protein, mouse; D019206:GTP-Binding Protein alpha Subunits, Gi-Go