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(Circulation Research. 2003;92:32.)
© 2003 American Heart Association, Inc.

Integrative Physiology

Relaxin, a Pregnancy Hormone, Is a Functional Endothelin-1 Antagonist

Attenuation of Endothelin-1–Mediated Vasoconstriction by Stimulation of Endothelin Type-B Receptor Expression via ERK-1/2 and Nuclear Factor-B

Thomas Dschietzig, Cornelia Bartsch, Christoph Richter, Michael Laule, Gert Baumann, Karl Stangl

From Medizinische Klinik und Poliklinik (Kardiologie, Angiologie, Pulmologie) Charité, Campus Mitte, Berlin, Germany.

Correspondence to Thomas Dschietzig, Medizinische Klinik und Poliklinik (Kardiologie, Angiologie, Pulmologie) Charité, Campus Mitte, Schumannstr. 20/21, 10098 Berlin, Germany. E-mail AnneDsch{at}aol.com

We have recently demonstrated that relaxin (RLX) acts as compensatory mediator in human heart failure. RLX inhibits the stimulation of endothelin-1, the most potent vasoconstrictor in heart failure. Upregulation of the endothelin type-B receptor (ET_B), which mediates endothelin-1 clearance and endothelial release of NO, represents a pivotal mode of RLX action. However, signal transduction and abundance of this phenomenon are unknown. Therefore, we investigated RLX-induced regulation of ET_B in human umbilical vein endothelial, epithelial (HeLa), and vascular smooth muscle cells. In human umbilical vein endothelial cells and HeLa cells, but not in human vascular smooth muscle cells, RLX upregulated ET_B expression and activated extracellular signal–regulated kinase-1/2 (ERK-1/2) and nuclear factor-B (NF-B), a transcription factor. PD-98059, a selective inhibitor of the mitogen-activated protein kinase kinase-1 (MEK-1)–ERK-1/2 pathway, abolished ERK-1/2 and NF-B activation and ET_B upregulation. NF-B inhibition also prevented RLX-mediated ET_B stimulation. In NF-B-luciferase reporter assays, we demonstrated complete inhibition of RLX-induced NF-B activation in cells transfected with dominant-negative Raf-1, MEK-1, or ERK-1/2 constructs, whereas dominant-negative Ras had no effect. In rat aorta and mesenteric artery, RLX pretreatment, in an ET_B-dependent fashion, mitigated the maximum contractile response to endothelin-1, by 38±4% and 43±6%, and the endothelin-1 sensitivity (-log[EC₅₀]: aorta, 8.2±0.2 for vehicle versus 7.2±0.2 for RLX; mesenteric artery, 8.0±0.2 for vehicle versus 7.1±0.1 for RLX). RLX pretreatment augmented the dilator effect of the ET_B agonist endothelin-3 by 100±8% and 133±13%. In conclusion, RLX stimulates endothelial and epithelial ET_B via a Ras-independent Raf-1–MEK-1–ERK-1/2 pathway that activates NF-B. On vascular smooth muscle cells, ET_B, a contributor to endothelin-mediated vasoconstriction, remains unaffected. This renders RLX a functional endothelin-1 antagonist.

Key Words: endothelin • receptors • signal transduction • vasoconstriction • vasodilation

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