CYCLIC GMP-DEPENDENT PROTEIN-KINASE REGULATES VASCULAR SMOOTH-MUSCLE CELL PHENOTYPE

Nitric oxide (NO) and cyclic guanosine 3',5'-monophosphate (cGMP) have been reported to prevent vascular smooth muscle cell (VSMC) prolifera tion and have beneficial effects to reduce intimal thickening in respo nse to arterial injury. The purpose of this study was to determine whe ther the downstream effector molecule of NO-cGMP signaling, cyclic GMP -dependent protein kinase (PKG), regulates phenotypic modulation and p roliferation in cultured rat aortic VSMC. PKG-expressing VSMC lines we re created by transfection of PKG-deficient cell lines and characteriz ed. All forms of PKG, i.e. PKG-I alpha and PKG-I beta, as well as the constitutively active catalytic domain of PKG-I, transformed dediffere ntiated 'synthetic' VSMC to a more contractile-like morphology. PKG ex pression resulted in an increased production of the contractile phenot ype marker proteins, smooth muscle myosin heavy chain-2, calponin and alpha-actin and restored the capacity of cAMP and cGMP analogues to in hibit platelet-derived growth factor (PDGF)-induced cell migration. On the other hand, PKG expression had no significant effects on PDGF-ind uced cell proliferation. These results suggest that PKG expression con tributes to the regulation of a contractile-like phenotypic expression in cultured VSMC, and the suppression of PKG expression during cultur ed growth in vitro may permit the modulation of cells to a more synthe tic, dedifferentiated phenotype.