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1 Krannert Institute of
Cardiology, Indiana University, Indianapolis, Indiana 46202;
2 Harvard Medical School,
Arterial smooth muscle stretch is an important physiological
modulator of vascular function. To identify intracellular processes altered during muscle stretch, we found previously that extracellular signal-regulated kinase-mitogen-activated protein kinase (MAPK) activity increased in response to the application of mechanical loads.
In the present study, stretch-dependent activation of MAPK in porcine
carotid arteries was investigated as was the phosphorylation of the
thin filament-binding protein caldesmon, which is known to be a
substrate for the kinase in fully differentiated smooth muscle. MAPK
activity was 67 pmol · min
1 · mg
protein1 in unloaded muscle
strips immediately after attachment to force transducers and 139 pmol · min1 · mg
protein1 within 30 s of
muscle stretch. When muscle strips were continually stretched, MAPK
activity remained elevated for ~2 h and then decreased over 16 h to
16 pmol · min1 · mg
protein1. When muscle
strips were stretched and then unloaded, MAPK activity decreased within
1 h to the level present in the muscle before the stretch. These
effects of muscle stretch on MAPK activity were additive to the effects
of KCl or phorbol ester stimulation and were partially inhibited by
reducing extracellular Ca2+.
Eliminating extracellular Ca2+ had
no effect on phorbol 12,13-dibutyrate (PDBu)-dependent contractions or
MAPK activity; however, KCl-dependent contractions and MAPK activity
were completely abolished by this procedure. An antibody specific for
detecting caldesmon phosphorylated by MAPK, vs. protein kinase C (PKC),
was developed and used to assess relative caldesmon phosphorylation in
unstimulated and PDBu-stimulated muscle strips. In all cases
investigated, the level of MAPK activity correlated with
phosphocaldesmon immunoreactivity. Because arterial MAPK activity is
regulated by PKC- and stretch-dependent mechanisms, these data are
consistent with a role for MAPK and the subsequent phosphorylation of
caldesmon as mediators in the stretch activation of vascular smooth
muscle.
smooth muscle; phorbol esters; caldesmon; phosphorylation; antibody
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