title: Aging-related alterations in eNOS and nNOS responsiveness and smooth muscle reactivity of murine basilar arteries are modulated by apocynin and phosphorylation of myosin phosphatase targeting subunit-1.
abstract: Aging causes major alterations of all components of the neurovascular unit and compromises brain blood supply. Here, we tested how aging affects vascular reactivity in basilar arteries from young (<10 weeks; y-BA), old (>22 months; o-BA) and old (>22 months) heterozygous MYPT1-T-696A/+ knock-in mice. In isometrically mounted o-BA, media thickness was increased by ∼10% while the passive length tension relations were not altered. Endothelial denudation or pan-NOS inhibition (100 µmol/L L-NAME) increased the basal tone by 11% in y-BA and 23% in o-BA, while inhibition of nNOS (1 µmol/L L-NPA) induced ∼10% increase in both ages. eNOS expression was ∼2-fold higher in o-BA. In o-BA, U46619-induced force was augmented (pEC50∼6.9 vs. pEC50∼6.5) while responsiveness to DEA-NONOate, electrical field stimulation or nicotine was decreased. Basal phosphorylation of MLC20-S19 and MYPT1-T-853 was higher in o-BA and was reversed by apocynin. Furthermore, permeabilized o-BA showed enhanced Ca2+-sensitivity. Old T-696A/+ BA displayed a reduced phosphorylation of MYPT1-T696 and MLC20, a lower basal tone in response to L-NAME and a reduced eNOS expression. The results indicate that the vascular hypercontractility found in o-BA is mediated by inhibition of MLCP and is partially compensated by an upregulation of endothelial NO release.
authors.affiliation: 1 Institute of Vegetative Physiology, University of Cologne, Germany.
authors.forename: Lubomir T
authors.initials: LT
authors.lastname: Lubomirov
authors.affiliation: 1 Institute of Vegetative Physiology, University of Cologne, Germany.
authors.forename: Symeon
authors.initials: S
authors.lastname: Papadopoulos
authors.affiliation: 1 Institute of Vegetative Physiology, University of Cologne, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pütz
authors.affiliation: 1 Institute of Vegetative Physiology, University of Cologne, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Welter
authors.affiliation: 2 Institute for Genetics, University of Cologne, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Klöckener
authors.affiliation: 1 Institute of Vegetative Physiology, University of Cologne, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Weckmüller
authors.affiliation: 1 Institute of Vegetative Physiology, University of Cologne, Germany.
authors.forename: Mostafa A
authors.initials: MA
authors.lastname: Ardestani
authors.affiliation: 1 Institute of Vegetative Physiology, University of Cologne, Germany.
authors.forename: Dilyana
authors.initials: D
authors.lastname: Filipova
authors.affiliation: 1 Institute of Vegetative Physiology, University of Cologne, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Metzler
authors.affiliation: 1 Institute of Vegetative Physiology, University of Cologne, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Metzner
authors.affiliation: 1 Institute of Vegetative Physiology, University of Cologne, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Staszewski
authors.affiliation: 1 Institute of Vegetative Physiology, University of Cologne, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zittrich
authors.affiliation: 3 Faculty of Biology, Sofia University St. Kliment Ohridski, Sofia, Bulgaria.
authors.forename: Hristo
authors.initials: H
authors.lastname: Gagov
authors.affiliation: 1 Institute of Vegetative Physiology, University of Cologne, Germany.
authors.forename: Mechthild M
authors.initials: MM
authors.lastname: Schroeter
authors.affiliation: 1 Institute of Vegetative Physiology, University of Cologne, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pfitzer
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D000375:Aging; D000818:Animals; D001488:Basilar Artery / Q000502:physiology*; D004791:Enzyme Inhibitors; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D043263:Myosin-Light-Chain Phosphatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation; D021122:Protein Subunits / Q000378:metabolism; D014661:Vasoconstriction
chemical_list: D000098:Acetophenones; D004791:Enzyme Inhibitors; D021122:Protein Subunits; C056165:acetovanillone; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496315:Nos3 protein, mouse; D043263:Myosin-Light-Chain Phosphatase
keywords: Aging; MYPT1-T696 gene mutation; actin dynamics; basilar artery; neurovascular uncoupling; vascular hypercontractility