CELL-CYCLE RELATED INHIBITION OF MOUSE VASCULAR SMOOTH-MUSCLE CELL-PROLIFERATION BY SMOOTH PROSTAGLANDIN E(1) RELATIONSHIP BETWEEN PROSTAGLANDIN E(1), AND INTRACELLULAR CAMP LEVELS

Elucidation of the cellular and molecular mechanisms which regulate va scular smooth muscle cell proliferation is critical to the understandi ng of atherogenesis. The present studies were conducted to evaluate th e relationship between prostaglandin E(1) (PGE(1)) and cAMP in the reg ulation of DNA synthesis in mouse vascular smooth muscle cells (SMCs). Quiescent cultures of SMCs were challenged with 10% fetal bovine seru m to initiate cell cycle transit and PGE(1) (10 mu M) or dibutyryl cAM P (1, 10, 100 mu M) added at 0, 8, 16, 24, and 32 h. DNA synthesis as measured by [H-3] thymidine incorporation and intracellular cAMP level s were measured 24 h following individual treatments. PGE(1) modulated DNA synthesis in a cell cycle related fashion, with inhibition only o bserved in cells challenged 16 h or longer following initiation of cel l cycle transit. The decrease in DNA synthesis induced by PGE, was ass ociated with increased intracellular cAMP levels at 16 and 24 h, but n ot 32 h. Exposure of SMCs to dibutyryl-cAMP also inhibited DNA synthes is in a cell cycle related fashion, with the most pronounced effect se en at 16 h. These results demonstrate that the effects of PGE(1) are r estricted to a defined period within the cell cycle following S phase entry and implicate modulation of intracellular cAMP levels in the inh ibitory response.