Copyright © 2006, European Society of Cardiology
Endothelin is a dose-dependent trophic factor and a mitogen in small arteries in vivo
aFaculty of Pharmacy, Université de Montréal, 2900 Édouard-Montpetit, Pavillon Jean-Coutu, room 3197, P.O. Box 6128, Station "Centre-Ville" Montréal, Québec, Canada H3C 3J7
bResearch Center, Hôtel-Dieu de Québec, Québec, Canada
cDepartment of Physiology, Faculty of Medicine, Université de Montréal, Montréal, Canada H3C 3J7
* Corresponding author. Tel.: +1 514 343 6111x3313; fax: +1 514 343 7073. Email address: Pierre.Moreau{at}Umontreal.ca
Objective Endothelin (ET) modulates cellular processes relevant to vascular remodeling, but there is still some debate as to the potential of ET to be a trophic factor or a mitogen. Moreover, the signaling of ET in vivo to produce these effects is largely unknown.
Methods 3H-leucine and 3H-thymidine incorporation in rat small mesenteric arteries was studied with several doses of ET-1 (0.1–10pmol/kg/min) administered for 26h in vivo.
Results The EC50 for protein synthesis was four times lower than that of DNA synthesis, with maximal effects around 1 and 3pmol/kg/min, respectively. At 5pmol/kg/min, ET enhanced CDK2 activity by reducing the binding of its inhibitor p27Kip1. In contrast, the binding was enhanced at 0.5pmol/kg/min. The reduced binding observed at 5pmol/kg/min could not be explained by changes of p27Kip1 or CDK2 content. Phosphorylation of p27Kip1 on serine 10 was significantly reduced at 5pmol/kg/min ET. Although the phosphoinositide 3-kinase pathway was activated, it did not contribute to the protein or DNA synthesis responses. Administration of 1 or 5pmol/kg/min ET-1 for 28days increased the thickness and cross-sectional area of the small mesenteric artery due to hypertrophy and hyperplasia, respectively, thus confirming the results obtained in acute conditions.
Conclusion ET modulates p27Kip1 binding to CDK2, producing hypertrophy at low and hyperplasia at higher concentrations. Taken together, these results suggest that ET can act both as a trophic factor and as a mitogen in an in vivo environment, depending on its local concentration.
KEYWORDS Endothelins; p27Kip1; Vascular remodeling; PI-3 Kinase; CDK2
Time for primary review 23 days
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