Affiliation:
1. From Cardiovascular Research (Z.Y., N.K., T.F.L.), Institute of Physiology, University Zürich-Irchel and Cardiology (Z.Y., T.F.L.), University Hospital Zürich, Switzerland.
Abstract
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 [
3
H]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 [
3
H]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 ET
A
receptor antagonist LU135252 and slightly further blocked by the ET
A/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 ET
A
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine
Cited by
146 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献