Key result
Endothelin-1 potentiates PDGF-BB-induced aortic smooth muscle proliferation up to ~6-fold via ETA receptors.
Why the study?
The mitogenic effects of endothelin-1 on human vascular smooth muscle cells and its interaction with PDGF remain controversial.
Does Endothelin-1 potentiate PDGF-induced proliferation in human aortic smooth muscle cells?
Does Endothelin-1 potentiate PDGF-induced proliferation in human aortic smooth muscle cells?
ET-1 has no direct mitogenic effect on human aortic smooth muscle cells but markedly potentiates PDGF-induced proliferation via ETA receptors, suggesting a mechanism for vascular structural changes.
BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor. However, its mitogenic effects on vascular smooth muscle cells (SMCs) remain controversial. We investigated the role of ET-1 in human SMC growth and its synergistic effect with platelet-derived growth factor (PDGF). METHODS AND RESULTS: Human aortic SMCs were cultured and cell proliferation was assayed by [3H]thymidine incorporation. PDGF receptor expression, activation of mitogen-activated protein kinase (MAPK), cell cycle regulators such as cyclin-dependent kinase 2 (Cdk2), Cdk inhibitor (p27(Kip1)), and retinoblastoma protein (pRb) were analyzed by immunoblotting. ET-1 on its own was unable to stimulate [3H]thymidine incorporation but dramatically potentiated the effect of PDGF-BB up to 6-fold (P<0.001). Most of the potentiating effects (88%) were blocked by the ETA receptor antagonist LU135252 and slightly further blocked by the ETA/B receptor antagonist bosentan (P<0.05). ET-1 stimulated MAPK, but it neither potentiated PDGF-induced MAPK activation nor overexpressed PDGF receptors. In contrast to PDGF-BB, ET-1 had no regulatory effects on Cdk2, p27(Kip1), and pRb. CONCLUSIONS: In human SMCs, ET-1 activates MAPK but has no mitogenic effects on its own. However, ET-1 markedly potentiates proliferation to PDGF, mainly via ETA receptors. This may represent an important function of ET-1 for vascular structural changes in patients and provide new therapeutic opportunities for ET-1 receptor antagonists.
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Yang et al. (1999) studied this question. Endothelin-1 (ET-1) was evaluated on Cell proliferation ([3H]thymidine incorporation) (6-fold potentiation, p=<0.001). Endothelin-1 dramatically potentiated the proliferative effect of PDGF-BB on human aortic smooth muscle cells up to 6-fold (P<0.001), primarily via ETA receptors.
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