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. Issue 3 (March 2017)

• Record Type: Journal Article
• Authors: Lubomirov, Lubomir T; Papadopoulos, Symeon; Pütz, Sandra; Welter, Johannes; Klöckener, Tim; Weckmüller, Kathrin; Ardestani, Mostafa A; Filipova, Dilyana; Metzler, Doris; Metzner, Harald; Staszewski, Jürgen; Zittrich, Stefan; Gagov, Hristo; Schroeter, Mechthild M; Pfitzer, Gabriele
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 37:Issue 3(2017)
• Page Start: 1014
• Page End: 1029
• Publication Date: 2017-03
• Subjects: Aging -- basilar artery -- vascular hypercontractility -- neurovascular uncoupling -- MYPT1-T696 gene mutation -- actin dynamics; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1177/0271678X16649402
• Languages: English
• ISSNs: 0271-678X

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 Ca 2+ -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.