Endothelin-1 Potentiates Human Smooth Muscle Cell Growth to PDGF

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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 A receptor antagonist LU135252 and slightly further blocked by the ET A/B receptor antagonist bosentan ( P 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.

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