TRANSFORMING GROWTH-FACTOR BETA-1 EXPRESSION AND EFFECT IN AORTIC SMOOTH-MUSCLE CELLS FROM SPONTANEOUSLY HYPERTENSIVE RATS

Previous studies demonstrated that in addition to an increased response to growth factors, cultured vascular smooth muscle cells derived from spontaneously hypertensive rats (SHRs) growth to a greater density than cells from normotensive Wistar-Kyoto (WKY) rats. Transforming growth factor beta-1 (TGF-beta-1) has a bimodal effect on vascular smooth muscle cell growth, depending on cell density. The present study investigated the relation between cell density and expression of the proto-oncogene c-fos and TGF-beta-1 in cells from WKY rats and SHRs. The results demonstrate an increased accumulation of c-fos mRNA in calf serum-stimulated SHR cells but only at a high cell density. The expression of TGF-beta-1 mRNA was enhanced in growing SHR cells at every density studied as early as 24 hours after inoculation, with a further increase at later times. The effect of exogenous TGF-beta-1 on new DNA synthesis was evaluated by [H-3]thymidine incorporation. At a low cell density, TGF-beta-1 had no effect on DNA synthesis in either WKY or SHR vascular smooth muscle cells. At a high cell density, there was a significant increase of DNA synthesis in response to TGF-beta-1 in SHR cells without any effect in WKY cells. In conclusion, contact inhibition of vascular smooth muscle cells from SHRs at a higher cell density is accompanied by an earlier expression of the marker gene c-fos and preceded by an exaggerated expression of TGF-beta-1. Considered together with the stimulating effect of exogenous TGF-beta-1 at a high cell density, the results suggest an abnormal feedback control (autocrine stimulation) of this growth factor and its involvement in altered contact inhibition of vascular smooth muscle cells from SHRs.