The proliferative responsiveness of human vascular smooth muscle cells to endothelin correlates with endothelin receptor density.
BACKGROUND
Endothelin (ET), a potent vasoconstrictor peptide, is implicated in disorders of intimal hyperplasia such as atherosclerosis and restenosis. Data from animal models and in vitro studies indicate that ET may act at the level of vascular smooth muscle cell proliferation. In this study the effect of ET on human vascular smooth muscle cells (HVSMC) was investigated.


METHODS
The mitogenic effect of ET on 30, early passage, HVSMC lines derived from normal donors and those undergoing aorto-coronary vein bypass grafting (ACVB) operation was examined and characterized. This was correlated with the density of endothelin receptors on these cells as well as with the rate of endothelin secretion.


RESULTS
There were no clear differences in the mitogenic responsiveness of cells from normal donors and those undergoing ACVB. In 10 HVSMC lines, DNA synthesis was significantly stimulated (30 to 120% stimulation above control, defined as responders), and an insignificant stimulation (< 30% above control) was observed in 20 cell lines (called non-responders); a similar pattern was observed in the cell multiplication assay. In the responder HVSMC lines, the rank order of ET isopeptides in stimulating mitogenesis was ET-1 = ET-2 > ET-3, and the effect was inhibited by the ET antagonist (BQ-123) suggesting that the ET-receptor-A (ETA) subtype was involved in mediating the actions of ET. Measurement of 125I-ET-1 binding to cells indicated there to be a strong correlation between the extent of ET mitogenic effect and receptor binding (N = 30, p = 0.034) but none with the rate of ET secretion.


CONCLUSIONS
These results suggest that increased levels of ET receptors on HVSMC, as observed in atherosclerotic plaques, may predispose them to ET-stimulated proliferation.
Kanse
S M
SM
Thrombosis Research Institute, London, United Kingdom.
Wijelath
E
E
Kanthou
C
C
Newman
P
P
Kakkar
V V
VV
D000293:Adolescent; D000328:Adult; D000368:Aged; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology*; D006801:Humans; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D010456:Peptides, Cyclic / Q000494:pharmacology; D017466:Receptors, Endothelin / Q000032:analysis*
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)