Aging- and growth-dependent modulation of endothelin-1 gene expression in human vascular endothelial cells.

Earlier we reported the undetectable level of endothelin (ET)-1 mRNA in aorta from young donors, in contrast to the detectable levels in older donors (Lab. Invest. 67, 210-217, 1992). We also found that the synthesis of ET-1 peptide is elevated in cultured endothelial cells from the aorta of over-50-year-old donors. In the present report, we show by in situ hybridization that the level of ET-1 mRNA is not so different in aortic endothelial cells from 5- and 50-year-old donors, but increases in cells from 76-year-old donors. The parallel results are obtained from Northern and in situ hybridization analyses by using serially passaged human umbilical vein endothelial cells. Thus, the increase of ET-1 peptide synthesis is achieved mainly at the level of mRNA. Furthermore, these results suggest that the increased expression of ET-1 in elderly people is due to the exhaustion of cell division potential of endothelial cells in vivo. We have also analyzed whether the expression of ET-1 is affected by the growth state. The data show that sparsely growing cells secrete more ET peptide than confluent and stationary cells. In situ hybridization also shows that S-phase cells express more ET-1 mRNA than non-S-phase cells. Thus, it is suggested that there are, at least, two ways for upregulation of ET-1 expression.