Mitogen-activated protein kinase activation: an alternate signaling pathway for sustained vascular smooth muscle contraction.
OBJECTIVE
The vascular smooth muscle determines the dynamic caliber of the blood vessel and hence is the final effector cell in modulating vasomotor tone. Although considerable information is available regarding the physiologic agonists that induce contraction, less is known about the cellular signaling events that lead to long-lasting contractions or vasospasm. We examined the hypothesis that activation of mitogen-activated protein (MAP) kinase may be associated with sustained smooth muscle contractions.


METHODS
Physiologic contractile responses were determined in intact bovine carotid artery smooth muscles in a muscle bath. Corresponding signaling events were determined with immunoblots using antiphosphotyrosine antibodies or immunoprecipitation of whole-cell phosphorylated strips of muscle.


RESULTS
The tyrosine kinase inhibitor, genestein, significantly inhibited the magnitude of contractions induced by phorbol ester, endothelin, angiotensin, and serotonin. In addition, genestein inhibited the sustained phase of contractions induced by serotonin. Serotonin-induced vascular smooth muscle contractions were temporally associated with an increase in the phosphorylation of MAP kinase.


CONCLUSIONS
These data suggest that the activation of MAP kinase is associated with sustained vascular smooth muscle contractions. Pharmacologic manipulation of MAP kinase activation may lead to new approaches to treat pathologic circumstances of increased vasomotor tone such as vasospasm.
Epstein
A M
AM
Department of Surgery, Medical College of Georgia, Augusta 30912, USA.
Throckmorton
D
D
Brophy
C M
CM
D000804:Angiotensin II / Q000037:antagonists & inhibitors; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D002339:Carotid Arteries; D002417:Cattle; D016232:Endothelins / Q000037:antagonists & inhibitors; D004789:Enzyme Activation / Q000187:drug effects; D019833:Genistein; D015151:Immunoblotting; D007529:Isoflavones / Q000494:pharmacology*; D008934:Mitogens / Q000502:physiology*; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D010703:Phorbol Esters / Q000737:chemistry; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012702:Serotonin Antagonists / Q000494:pharmacology
D002148:Calmodulin-Binding Proteins; D016232:Endothelins; D007529:Isoflavones; D008934:Mitogens; D010703:Phorbol Esters; D012702:Serotonin Antagonists; D000804:Angiotensin II; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases