Abstract
Intracellular signaling mechanisms affected by endothelin (ET), a hypertrophic agonist, and platelet-derived growth factor (PDGF)-BB, a proliferative agonist, in vascular smooth muscle cells were examined. PDGF-BB was a potent mitogen compared with untreated cultures, stimulating both [3H]thymidine incorporation and cell number. In contrast, ET was a poor mitogen, enhancing [3H]thymidine incorporation but not cell number. Simultaneous ET and PDGF-BB treatment was significantly more effective than either agonist alone at stimulating both [3H]thymidine uptake and cell number. Although either ET or PDGF-BB alone stimulated arachidonic acid release, phosphoinositide hydrolysis, protein kinase C activation, PDGF receptor phosphorylation, and mitogen-activated protein kinase activity, of these effectors, only arachidonic acid release was further enhanced by simultaneous ET and PDGF-BB treatment. These results link proliferative and hypertrophic signal transduction pathways in these cells and suggest that arachidonic acid or its metabolites mediate the observed effects of ET on PDGF-BB-stimulated vascular smooth muscle cell proliferation.
MeSH terms
-
Animals
-
Arachidonic Acid / metabolism*
-
Becaplermin
-
Calcium-Calmodulin-Dependent Protein Kinases / metabolism
-
Cells, Cultured
-
DNA / biosynthesis*
-
Endothelins / pharmacology*
-
Inositol 1,4,5-Trisphosphate / metabolism
-
Intracellular Signaling Peptides and Proteins*
-
Membrane Proteins*
-
Mitogen-Activated Protein Kinase 1
-
Mitogen-Activated Protein Kinase 3
-
Mitogen-Activated Protein Kinases*
-
Muscle, Smooth, Vascular / cytology
-
Muscle, Smooth, Vascular / metabolism*
-
Myristoylated Alanine-Rich C Kinase Substrate
-
Phosphorylation
-
Platelet-Derived Growth Factor / pharmacology*
-
Protein Kinase C / metabolism
-
Proteins / metabolism
-
Proto-Oncogene Proteins c-sis
-
Rabbits
-
Receptors, Platelet-Derived Growth Factor / metabolism
-
Signal Transduction
-
Thymidine / pharmacokinetics
-
Type C Phospholipases / metabolism
Substances
-
Endothelins
-
Intracellular Signaling Peptides and Proteins
-
Membrane Proteins
-
Platelet-Derived Growth Factor
-
Proteins
-
Proto-Oncogene Proteins c-sis
-
Myristoylated Alanine-Rich C Kinase Substrate
-
Becaplermin
-
Arachidonic Acid
-
Inositol 1,4,5-Trisphosphate
-
DNA
-
Receptors, Platelet-Derived Growth Factor
-
Protein Kinase C
-
Calcium-Calmodulin-Dependent Protein Kinases
-
Mitogen-Activated Protein Kinase 1
-
Mitogen-Activated Protein Kinase 3
-
Mitogen-Activated Protein Kinases
-
Type C Phospholipases
-
Thymidine