title: Inducible human endothelin-1 overexpression in endothelium raises blood pressure via endothelin type A receptors.
abstract: The mechanisms of blood pressure regulation by endothelin-1 produced by endothelial cells are complex and still unclear. Transgenic mice with endothelium-restricted human endothelin-1 (EDN1) overexpression presented vascular damage but no significant change in blood pressure, which could be because of adaptation to life-long exposure to elevated endothelin-1 levels. We now generated a tamoxifen-inducible endothelium-restricted EDN1 overexpressing transgenic mouse (ieET-1) using Cre/loxP technology. Sixteen days after tamoxifen treatment, ieET-1 mice presented ≥10-fold increase in plasma endothelin-1 (P<0.01) and ≥20 mm Hg elevation in systolic blood pressure (P<0.01), which could be reversed by atrasentan (P<0.05). Endothelin-1 overexpression did not cause vascular or kidney injury or changes in kidney perfusion or function. However, endothelin type A and B receptor expression was differentially regulated in the mesenteric arteries and the kidney. Our results demonstrate using this ieET-1 mouse model that 21 days of induction of endothelin-1 overexpression caused endothelin-1-dependent elevated blood pressure mediated by endothelin type A receptors.
authors.affiliation: From the Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research (Y.R., S.C.C., J.C.F.-A., K.-G.H., A.R., P.P., E.L.S.) and Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital (E.L.S.), McGill University, Montreal, Quebec, Canada; and Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Nauheim, Germany (S.O.).
authors.forename: Yohann
authors.initials: Y
authors.lastname: Rautureau
authors.affiliation: From the Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research (Y.R., S.C.C., J.C.F.-A., K.-G.H., A.R., P.P., E.L.S.) and Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital (E.L.S.), McGill University, Montreal, Quebec, Canada; and Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Nauheim, Germany (S.O.).
authors.forename: Suellen C
authors.initials: SC
authors.lastname: Coelho
authors.affiliation: From the Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research (Y.R., S.C.C., J.C.F.-A., K.-G.H., A.R., P.P., E.L.S.) and Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital (E.L.S.), McGill University, Montreal, Quebec, Canada; and Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Nauheim, Germany (S.O.).
authors.forename: Julio C
authors.initials: JC
authors.lastname: Fraulob-Aquino
authors.affiliation: From the Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research (Y.R., S.C.C., J.C.F.-A., K.-G.H., A.R., P.P., E.L.S.) and Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital (E.L.S.), McGill University, Montreal, Quebec, Canada; and Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Nauheim, Germany (S.O.).
authors.forename: Ku-Geng
authors.initials: KG
authors.lastname: Huo
authors.affiliation: From the Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research (Y.R., S.C.C., J.C.F.-A., K.-G.H., A.R., P.P., E.L.S.) and Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital (E.L.S.), McGill University, Montreal, Quebec, Canada; and Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Nauheim, Germany (S.O.).
authors.forename: Asia
authors.initials: A
authors.lastname: Rehman
authors.affiliation: From the Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research (Y.R., S.C.C., J.C.F.-A., K.-G.H., A.R., P.P., E.L.S.) and Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital (E.L.S.), McGill University, Montreal, Quebec, Canada; and Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Nauheim, Germany (S.O.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: From the Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research (Y.R., S.C.C., J.C.F.-A., K.-G.H., A.R., P.P., E.L.S.) and Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital (E.L.S.), McGill University, Montreal, Quebec, Canada; and Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Nauheim, Germany (S.O.).
authors.forename: Pierre
authors.initials: P
authors.lastname: Paradis
authors.affiliation: From the Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research (Y.R., S.C.C., J.C.F.-A., K.-G.H., A.R., P.P., E.L.S.) and Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital (E.L.S.), McGill University, Montreal, Quebec, Canada; and Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Nauheim, Germany (S.O.). ernesto.schiffrin@mcgill.ca.
authors.forename: Ernesto L
authors.initials: EL
authors.lastname: Schiffrin
mesh_terms: D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011759:Pyrrolidines / Q000494:pharmacology; D044022:Receptor, Endothelin A / Q000378:metabolism*; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: C000588596:EDNRB protein, human; D019332:Endothelin-1; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D013629:Tamoxifen; D000077868:Atrasentan
keywords: blood pressure; endothelin receptors type A; endothelin-1; endothelium; mice, transgenic