title: Smooth muscle specific disruption of the endothelin-A receptor in mice reduces arterial pressure, and vascular reactivity and affects vascular development.
abstract: OBJECTIVE
  The role of vascular smooth muscle endothelin A receptors (ETA) in development and normal physiology remains incompletely understood. To address this, mice were generated with smooth muscle-specific knockout (KO) of ETA.
  
  
  METHODS
  Mice were homozygous for loxP-flanked exons 6-8 of the EDNRA gene (floxed) or were also hemizygous for a transgene expressing Cre recombinase under control of the smooth muscle-specific SM22 promoter (KO mice).
  
  
  RESULTS
  Genotyping at 17 days postnatal yielded a 10:1 ratio of floxed:KO mice. Smooth muscle actin staining of embryos at day E10.5 revealed increased tortuosity in dorsal aortae while E12.5 embryos had mandibular, vascular and thymic abnormalities. Mice surviving to weaning developed and bred normally. ETA KO mice aged 2-3 months manifested EDNRA gene recombination in all organs tested. Aortas from KO mice had a >90% reduction in ETA mRNA content, but no differences in ET-1 or ETB mRNA levels. Addition of 0.01-100 nM ET-1 to isolated femoral arteries from floxed, but not KO, mice dose-dependently decreased vessel diameter (up to 80% reduction in the presence of ETB blockade). Intravenous infusion of ET-1 into floxed, but not KO, mice increased mean arterial pressure (MAP) (by ~10 mm Hg). Telemetric analysis revealed decreased MAP in KO mice (reduced by ~7-10 mm Hg) when fed a high salt diet.
  
  
  CONCLUSIONS
  Smooth muscle ETA is important for normal vascular, mandibular and thymic development and is involved in the maintenance of arterial pressure under physiological conditions.
authors.affiliation: George E. Wahlen Department of Veterans Affairs Medical Center, Geriatric Research Education and Clinical Center, 500 Foothill Drive, Salt Lake City, UT 84148, USA; Department of Internal Medicine, University of Utah School of Medicine, University of Utah, 30 N. 1900 E. AB193 SOM, Salt Lake City, UT 84132-0001, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Donato
authors.affiliation: George E. Wahlen Department of Veterans Affairs Medical Center, Geriatric Research Education and Clinical Center, 500 Foothill Drive, Salt Lake City, UT 84148, USA; Department of Internal Medicine, University of Utah School of Medicine, University of Utah, 30 N. 1900 E. AB193 SOM, Salt Lake City, UT 84132-0001, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Lesniewski
authors.affiliation: Department of Internal Medicine, University of Utah School of Medicine, University of Utah, 30 N. 1900 E. AB193 SOM, Salt Lake City, UT 84132-0001, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Stuart
authors.affiliation: Department of Internal Medicine, University of Utah School of Medicine, University of Utah, 30 N. 1900 E. AB193 SOM, Salt Lake City, UT 84132-0001, USA.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Walker
authors.affiliation: Department of Internal Medicine, University of Utah School of Medicine, University of Utah, 30 N. 1900 E. AB193 SOM, Salt Lake City, UT 84132-0001, USA.
authors.forename: Grant
authors.initials: G
authors.lastname: Henson
authors.affiliation: Department of Internal Medicine, University of Utah School of Medicine, University of Utah, 30 N. 1900 E. AB193 SOM, Salt Lake City, UT 84132-0001, USA.
authors.forename: Lise
authors.initials: L
authors.lastname: Sorensen
authors.affiliation: George E. Wahlen Department of Veterans Affairs Medical Center, Geriatric Research Education and Clinical Center, 500 Foothill Drive, Salt Lake City, UT 84148, USA; Department of Human Genetics, Eccles Institute of Human Genetics, University of Utah, Building 533, Rm 2100, 15 North 2030 East, Salt Lake City, UT 84112, USA.
authors.forename: Dean
authors.initials: D
authors.lastname: Li
authors.affiliation: George E. Wahlen Department of Veterans Affairs Medical Center, Geriatric Research Education and Clinical Center, 500 Foothill Drive, Salt Lake City, UT 84148, USA. Electronic address: donald.kohan@hsc.utah.edu.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Kohan
mesh_terms: D000818:Animals; D062186:Arterial Pressure; D001835:Body Weight; D017353:Gene Deletion; D006439:Hemodynamics; D006973:Hypertension / Q000503:physiopathology; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000254:growth & development* / Q000378:metabolism / Q000503:physiopathology*; D009929:Organ Size; D009928:Organ Specificity; D044022:Receptor, Endothelin A / Q000172:deficiency* / Q000378:metabolism; D015203:Reproducibility of Results; D017673:Sodium Chloride, Dietary; D014661:Vasoconstriction
chemical_list: D044022:Receptor, Endothelin A; D017673:Sodium Chloride, Dietary
keywords: Endothelin A receptor; Endothelin-1; Vascular smooth muscle