title: Endothelial function in aorta segments of apolipoprotein E-deficient mice before development of atherosclerotic lesions.
abstract: Acetylcholine (ACh)-induced relaxation declines in apolipoprotein E-deficient (apoE-/-) mouse aortas, but only after atherosclerotic plaque formation. This study investigated intracellular calcium concentrations [Ca2+]i and changes in phenylephrine-induced contractions as index of baseline nitric oxide (NO) bioavailability before plaque development. Isometric contractions of thoracic aorta rings of young (4 months) apoE-/- and C57BL/6J (WT) mice were evoked by phenylephrine (3x10(-9)-3x10(-5) M) in the presence and absence of endothelial cells (ECs) or NO synthase (NOS) inhibitors. [Ca2+]i (Fura-2 AM) and endothelium-dependent relaxation were measured at baseline and after ACh stimulation. Segments of apoE-/- mice were significantly more sensitive and developed more tension than WT segments in response to phenylephrine. The differences disappeared after NOS inhibition or EC removal or upon increasing [Ca2+]i in apoE-/- strips with 10(-6) M cyclopiazonic acid or 10(-7) M Ca2+-ionophore A23187. Expression of endothelial NOS (eNOS) mRNA was similar in apoE-/- and WT aorta segments. Basal [Ca2+]i was significantly lower in apoE-/- than in WT strips. Relaxation by ACh (3x10(-9)-10(-5) M) was time- and dose-dependently related to [Ca2+]i, but neither ACh-induced relaxation nor Ca2+ mobilization were diminished in apoE-/- strips. In conclusion, basal, but not ACh-induced NO bioavailability, was compromised in lesion-free aorta of apoE-/- mice. Decreased basal NO bioavailability was not related to lower eNOS expression, but most likely related to lower basal [Ca2+]i. These findings further point to important differences between basal and stimulated eNOS activity.
authors: Division of Pharmacology, Faculties of Medicine and Pharmaceutical Sciences, University of Antwerp, Campus Drie Eiken, Gebouw T, Universiteitsplein 1, Wilrijk, 2610, Belgium. paul.fransen@ua.ac.be
authors: Paul
authors: P
authors: Fransen
authors: Tim
authors: T
authors: Van Assche
authors: Pieter-Jan
authors: PJ
authors: Guns
authors: Cor E
authors: CE
authors: Van Hove
authors: Gilles W
authors: GW
authors: De Keulenaer
authors: Arnold G
authors: AG
authors: Herman
authors: Hidde
authors: H
authors: Bult
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology / Q000473:pathology / Q000502:physiology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D004730:Endothelium, Vascular / Q000201:enzymology / Q000473:pathology / Q000502:physiology*; D005260:Female; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D010656:Phenylephrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D000109:Acetylcholine; D002118:Calcium