Smooth muscle specific disruption of the endothelin-A receptor in mice reduces arterial pressure, and vascular reactivity and affects vascular development

Aims: 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. Main methods: Mice were homozygous for loxP-flanked exons 6-8 of the EDNRA gene (foxed) or were also hemizygous for a transgene expressing Cre recombinase under control of the smooth muscle-specific SM22 promoter (1(0 mice). Key findings: 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 1(0 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 foxed, but not KO, mice dose-dependently decreased vessel diameter (up to 80% reduction in the presence of FIB blockade). Intravenous infusion of ET-1 into foxed, but not KO, mice increased mean arterial pressure (MAP) (by similar to 10 mm Hg). Telemetric analysis revealed decreased MAP in KO mice (reduced by similar to 7-10 mm Hg) when fed a high salt diet. Significance: Smooth muscle ETA is important for normal vascular, mandibular and thymic development and is involved in the maintenance of arterial pressure under physiological conditions. (C) 2014 The Authors. Published by Elsevier Inc.