Endothelin-1 (ET-1), a vasoconstrictor peptide produced by endothelial
and vascular smooth muscle cells (VSMC) might play a role in vascular
remodelling. To investigate the proposed 'mitogenic' potential of ET-
1, we examined the effects of chronic exposure of VSMC to ET-1 on cell
cycle, growth/proliferation and differentiation under essentially mit
ogen-free culture conditions. Bulk cultures of thoracic aortic VSMC of
spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY)
rats, although exhibiting genetically determined differences in growth
/proliferation (due to shortened G1 and G2 phases in SHR VSMC), respon
d in a similar manner to ET-1 exposure: long-term exposure (12-15 days
) of VSMC from both sources to ET-1 in nonmitogenic medium did not pro
mote cycling of cells. On the contrary, ET-1 attenuated the cycling of
VSMC which had already cycled beyond the S phase. For cells which had
not cycled beyond the S phase, ET-1 interrupted progression through t
he cell cycle at the late G1/early S phase. The specific ability of SH
R VSMC to grow in mitogen-free medium was abolished by ET-1, most like
ly via down-regulation of platelet-derived growth factor (PDGF)-alpha
receptors. Subsequent to ET-1 exposure, VSMC expressed increased level
s of mRNA and protein for smooth-muscle-specific alpha-actin. However,
expression of smooth muscle alpha-actin did not predominate over beta
-actin as observed for adult contractile VSMC in vivo. The ET-1-induce
d expression of smooth-muscle-specific alpha-actin mRNA was dose depen
dent (EC50 approx. 2 x 10(-9) M), and alpha-actin protein expressed wa
s associated with organized actin fibers.