Abstract
Background:
RhoA and Rho kinase are important modulators of microvascular tone.
Methods and results:
We tested whether sphingosine kinase (Sphk1) that generates the endogenous sphingolipid mediator sphingosine-1-phosphate (S1P) is part of a signaling cascade to activate the RhoA/Rho kinase pathway. Using a new transfection model, we report that resting tone and myogenic responses of isolated resistance arteries increased with forced expression of Sphk1 in smooth muscle cells of these arteries. Overexpression of a dominant negative Sphk1 mutant or coexpression of dominant negative mutants of RhoA or Rho kinase together with Sphk1 completely inhibited development of tone and myogenic responses.
Conclusions:
The tone-increasing effects of a Sphk1 overexpression suggest that Sphk1 may play an important role in the control of peripheral resistance.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arteries / cytology
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Arteries / drug effects
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Arteries / physiology*
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Cricetinae
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Culture Techniques
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Enzyme Activation / physiology
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Genes, Dominant
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Green Fluorescent Proteins
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Intracellular Signaling Peptides and Proteins
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Luminescent Proteins / genetics
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Microcirculation / physiology*
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Muscle, Skeletal / blood supply
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / metabolism*
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Phosphotransferases (Alcohol Group Acceptor) / biosynthesis
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Phosphotransferases (Alcohol Group Acceptor) / genetics
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Phosphotransferases (Alcohol Group Acceptor) / physiology*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / physiology
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Transfection
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Vasoconstriction / physiology
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Vasomotor System / physiology
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rho-Associated Kinases
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rhoA GTP-Binding Protein / genetics
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rhoA GTP-Binding Protein / metabolism*
Substances
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Intracellular Signaling Peptides and Proteins
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Luminescent Proteins
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Recombinant Fusion Proteins
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Green Fluorescent Proteins
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Phosphotransferases (Alcohol Group Acceptor)
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sphingosine kinase
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Protein Serine-Threonine Kinases
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rho-Associated Kinases
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rhoA GTP-Binding Protein