CALCIUM-ANTAGONISTS DIFFERENTLY INHIBIT PROLIFERATION OF HUMAN CORONARY SMOOTH-MUSCLE CELLS IN RESPONSE TO PULSATILE STRETCH AND PLATELET-DERIVED GROWTH-FACTOR

Background. Vascular smooth muscle cell proliferation is the key event of coronary artery disease. Mechanical forces, in particular, pulsatile stretch and platelet-derived growth factor, may play an important role. Methods and Results. Vascular smooth muscle cells were cultured from the media of human left descending coronary arteries obtained from organ donors using the explant method. To study effects of pulsatile stretch on vascular smooth muscle cell proliferation, a computer-controlled in vitro pulsatile stretch device was used. Cells were seeded onto Flex I culture plates with deformable membranes and exposed to pulsatile stretch (60 cycles per minute) and/or growth factors. Proliferation of smooth muscle cells was determined by H-3-thymidine incorporation. Pulsatile stretch markedly stimulated H-3-thymidine incorporation of coronary smooth muscle cells (180+/-15 to 432+/-27 cpm/10(5) cells; P<.05) after 24 hours and increased cell number after 6 days (10.3+/-0.7x10(4)/mL to 11.7+/-0.5x10(4)/mL; P<.05). Platelet-derived growth factor-AB (0.01 to 10 ng/mL) concentration-dependently stimulated H-3-thymidine incorporation in coronary smooth muscle cells (EC50, 0.1 ng/mL) and had additive effects with pulsatile stretch. The Ca2+ antagonist verapamil (10(-7) to 10(-5) M) concentration-dependently inhibited proliferation stimulated by platelet-derived growth factor back to control levels (P<.05 to .01) but not that induced by pulsatile stretch. Conclusions. Pulsatile stretch and platelet-derived growth factor are potent stimuli for proliferation of coronary smooth muscle cells. The selective inhibitory effect of a Ca2+ antagonist on smooth muscle cell proliferation stimulated by platelet-derived growth factor but not by pulsatile stretch may explain why the drugs have only modest antiatherogenic effects in patients with coronary artery disease.