Endothelin-1 potentiates human smooth muscle cell growth to PDGF: effects of ETA and ETB receptor blockade.
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).


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.
Yang
Z
Z
Cardiovascular Research, Institute of Physiology, University Zürich-Irchel and Cardiology, University Hospital Zürich, Switzerland.
Krasnici
N
N
Lüscher
T F
TF
D001011:Aorta / Q000166:cytology; D000077214:Becaplermin; D042846:CDC2-CDC28 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D004357:Drug Synergism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017479:Receptors, Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000235:genetics; D016160:Retinoblastoma Protein / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D008869:Microtubule-Associated Proteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077214:Becaplermin; D017479:Receptors, Platelet-Derived Growth Factor; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases