ENDOTHELIN AND PDGF ENHANCE ARACHIDONIC-ACID RELEASE AND DNA-SYNTHESIS IN VASCULAR SMOOTH-MUSCLE CELLS

Intracellular signaling mechanisms affected by endothelin (ET), a hype rtrophic agonist, and platelet-derived growth factor (PDGF)-BB, a prol iferative agonist; in vascular smooth muscle cells were examined. PDGF -BB was a potent mitogen compared with untreated cultures, stimulating both [H-3]thymidine incorporation and cell number. In contrast; ET wa s a poor mitogen, enhancing [H-3]thymidine incorporation but not cell number. Simultaneous ET and PDGF-BB treatment was significantly more e ffective than either agonist alone at stimulating both [H-3]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 pr otein kinase activity, of these effecters, only arachidonic acid relea se was further enhanced by simultaneous ET and PDGF-BB treatment. Thes e results link proliferative and hypertrophic signal transduction path ways in these cells and suggest that arachidonic acid or its metabolit es mediate the observed effects of ET on PDGF-BB-stimulated vascular s mooth muscle cell proliferation.