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Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Charité University Hospital, Humboldt University of Berlin, 13125 Berlin; and Medical School Hannover, Department of Nephrology, D-30625 Hannover, Germany
The
initiation of contractile force in arterial smooth muscle (SM) is
believed to be regulated by the intracellular Ca2+
concentration and SM myosin type II phosphorylation. We tested the
hypothesis that SM myosin type II operates as a molecular motor protein
in electromechanical, but not in protein kinase C (PKC)-induced,
contraction of small resistance-sized cerebral arteries. We utilized a
SM type II myosin heavy chain (MHC) knockout mouse model and measured
arterial wall Ca2+ concentration
([Ca2+]i) and the diameter of pressurized
cerebral arteries (30-100 µm) by means of digital fluorescence
video imaging. Intravasal pressure elevation caused a graded
[Ca2+]i increase and constricted cerebral
arteries of neonatal wild-type mice by 20-30%. In contrast,
intravasal pressure elevation caused a graded increase of
[Ca2+]i without constriction in (
/)
MHC-deficient arteries. KCl (60 mM) induced a further
[Ca2+]i increase but failed to induce
vasoconstriction of (/) MHC-deficient cerebral arteries. Activation
of PKC by phorbol ester (phorbol 12-myristate 13-acetate, 100 nM)
induced a strong, sustained constriction of (/) MHC-deficient
cerebral arteries without changing [Ca2+]i.
These results demonstrate a major role for SM type II myosin in the
development of myogenic tone and Ca2+-dependent
constriction of resistance-sized cerebral arteries. In contrast, the
sustained contractile response did not depend on myosin and
intracellular Ca2+ but instead depended on PKC. We suggest
that SM myosin type II operates as a molecular motor protein in the
development of myogenic tone but not in pharmacomechanical coupling by
PKC in cerebral arteries. Thus PKC-dependent phosphorylation of
cytoskeletal proteins may be responsible for sustained contraction in
vascular SM.
protein kinase C; pressurized cerebral arteries; phorbol ester; arterial tone; myosin heavy chain; knockout mouse
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