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

Abstract

AimsThe 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 methodsMice 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). Key findingsGenotyping at 17days 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 2–3months 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 0.01–100nM 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 ~10mmHg). Telemetric analysis revealed decreased MAP in KO mice (reduced by ~7–10mmHg) when fed a high salt diet. SignificanceSmooth muscle ETA is important for normal vascular, mandibular and thymic development and is involved in the maintenance of arterial pressure under physiological conditions.