TGF-BETA-1 POTENTIATES GROWTH FACTOR-STIMULATED PROLIFERATION OF VASCULAR SMOOTH-MUSCLE CELLS IN GENETIC-HYPERTENSION

We have examined the interactions between transforming growth factor-beta-1 (TGF-beta-1) and epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), or platelet-derived growth factor (PDGF) isoforms PDGF-AB and PDGF-BB on the proliferation of vascular smooth muscle cells isolated from the spontaneously hypertensive rat. TGF-beta-1 alone stimulated [H-3]thymidine incorporation approximately twofold without a corresponding increase in cell number. In combination, TGF-beta-1 action was synergistic in further stimulating both DNA synthesis and cell proliferation 100-300% above the responses elicited by each growth factor. To gain further insight into the mechanism responsible for this potentiation, we examined the interaction between TGF-beta-1 and EGF. The synergistic interaction between TGF-beta-1 and EGF on DNA synthesis was independent of initial cell density. This effect of TGF-beta-1 was initiated early in the G1 phase of the cell cycle and did not appear to be mediated through the mobilization of Ca2+ or alterations in c-jun mRNA expression. However, in the presence of both TGF-beta-1 and EGF, there was a sustained elevation of c-myc mRNA levels over a 24-h period. These results suggest that TGF-beta-1 may interact with other growth factors in vivo to enhance their proliferative action on vascular smooth muscle of spontaneously hypertensive rats via mechanisms dependent on c-myc mRNA expression.