title: Endothelial overexpression of endothelin-1 modulates aortic, carotid, iliac and renal arterial responses in obese mice.
abstract: Endothelin-1 (ET-1) is essential for mammalian development and life, but it has also been implicated in increased cardiovascular risk under pathophysiological conditions. The aim of this study was to determine the impact of endothelial overexpression of the prepro-endothelin-1 gene on endothelium-dependent and endothelium-independent responses in the conduit and renal arteries of lean and obese mice. Obesity was induced by high-fat-diet (HFD) consumption in mice with Tie-1 promoter-driven, endothelium-specific overexpression of the prepro-endothelin-1 gene (TEThet) and in wild-type (WT) littermates on a C57BL/6N background. Isometric tension was measured in rings (with endothelium) of the aorta (A), carotid (CA) and iliac (IA) arteries as well as the main (MRA) and segmental renal (SRA) arteries; all experiments were conducted in the absence or presence of L-NAME and/or the COX inhibitor meclofenamate. The release of prostacyclin and thromboxane A2 was measured by ELISA. In the MRA, TEThetper se increased contractions to endothelin-1, but the response was decreased in SRA in response to serotonin; there were also improved relaxations to acetylcholine but not insulin in the SRA in the presence of L-NAME. HFD per se augmented the contractions to endothelin-1 (MRA) and to the thromboxane prostanoid (TP) receptor agonist U46619 (CA, MRA) as well as facilitated relaxations to isoproterenol (A). The combination of HFD and TEThetoverexpression increased the contractions of MRA and SRA to vasoconstrictors but not in the presence of meclofenamate; this combination also augmented further relaxations to isoproterenol in the A. Contractions to endothelin-1 in the IA were prevented by endothelin-A receptor antagonist BQ-123 but only attenuated in obese mice by BQ-788. The COX-1 inhibitor FR122047 abolished the contractions of CA to acetylcholine. The release of prostacyclin during the latter condition was augmented in samples from obese TEThetmice and abolished by FR122047. These findings suggest that endothelial TEThetoverexpression in lean animals has minimal effects on vascular responsiveness. However, if comorbid with obesity, endothelin-1-modulated, prostanoid-mediated renal arterial dysfunction becomes apparent.
authors.affiliation: Department of Pharmacology & Pharmacy, the University of Hong Kong, Hong Kong SAR, China.|State Key Laboratory of Pharmaceutical Biotechnology, the University of Hong Kong, Hong Kong SAR, China.
authors.forename: Oliver
authors.initials: O
authors.lastname: Baretella
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, the University of Hong Kong, Hong Kong SAR, China.|School of Biomedical Sciences, the University of Hong Kong, Hong Kong SAR, China.|Research Centre of Heart, Brain, Hormone & Healthy Aging, the University of Hong Kong, Hong Kong SAR, China.
authors.forename: Sookja K
authors.initials: SK
authors.lastname: Chung
authors.affiliation: Department of Pharmacology & Pharmacy, the University of Hong Kong, Hong Kong SAR, China.|State Key Laboratory of Pharmaceutical Biotechnology, the University of Hong Kong, Hong Kong SAR, China.|Research Centre of Heart, Brain, Hormone & Healthy Aging, the University of Hong Kong, Hong Kong SAR, China.|Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.affiliation: Department of Pharmacology & Pharmacy, the University of Hong Kong, Hong Kong SAR, China.|State Key Laboratory of Pharmaceutical Biotechnology, the University of Hong Kong, Hong Kong SAR, China.|Research Centre of Heart, Brain, Hormone & Healthy Aging, the University of Hong Kong, Hong Kong SAR, China.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Vanhoutte
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology; D001158:Arteries / Q000378:metabolism* / Q000503:physiopathology; D002339:Carotid Arteries / Q000378:metabolism / Q000503:physiopathology; D051545:Cyclooxygenase 1; D059305:Diet, High-Fat / Q000009:adverse effects; D042783:Endothelial Cells / Q000378:metabolism*; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology; D019332:Endothelin-1 / Q000378:metabolism*; D007083:Iliac Artery / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D008822:Mice, Transgenic; D009119:Muscle Contraction; D009126:Muscle Relaxation; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D017482:Receptors, Thromboxane / Q000378:metabolism; D012077:Renal Artery / Q000378:metabolism / Q000503:physiopathology; D013928:Thromboxane A2 / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D008565:Membrane Proteins; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; D013928:Thromboxane A2; D019001:Nitric Oxide Synthase; D051545:Cyclooxygenase 1; C496512:Ptgs1 protein, mouse; D000109:Acetylcholine