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This Article Summary Full Text Full Text (PDF) All Versions of this Article: fj.05-5328fjev1 20/11/1936    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chansel, D. Articles by Tharaux, P.-L. Search for Related Content PubMed PubMed Citation Articles by Chansel, D. Articles by Tharaux, P.-L.

Heparin binding EGF is necessary for vasospastic response to endothelin

Dominique Chansel^*,1, Magali Ciroldi¹, Sophie Vandermeersch^*, Leslie F Jackson, Ana-Maria Gomez, Daniel Henrion, David C. Lee, Thomas M. Coffman^||, Sylvain Richard, Jean-Claude Dussaule^*, and Pierre-Louis Tharaux^*,2

^* INSERM U702; Hôpital Tenon; Université Pierre et Marie Curie, Paris, France;

Department of Biochemistry and Biophysics, UNC Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA;

INSERM U637; Université Montpellier 1; CHU Arnaud de Villeneuve, France;

CNRS UMR 6188; Faculté de Médecine, Université d’Angers, Angers, France;

^|| Division of Nephrology, Department of Medicine, Duke University and Durham Veterans Affairs Medical Center, Durham, North Carolina, USA; and

Université Pierre et Marie Curie, AP-HP; School of Medicine Saint-Antoine, Paris, France

²Correspondence. INSERM U702, Hôpital Tenon, Université Pierre et Marie Curie, 4 rue de la Chine, Paris 75020, France. E-mail: pierre-louis.tharaux{at}chusa.jussieu.fr

ABSTRACT

Endothelin-1 (ET-1), a powerful vasoconstrictor, is involved in vasospastic diseases such as coronary artery disease and subarachnoidal hemorrhage, as well as in renal and cardiovascular fibrotic remodeling. Transactivation of the epidermal growth factor receptor (EGFR) mediates ET-1 signaling in vascular smooth muscle cells (VSMCs) and isolated arteries. Moreover, EGFR is required for a full constrictive response to ET-1. However, the relevant mechanisms mediating EGFR transactivation in response to ET-1 have not been identified. The present study used isolated arteries and VSMCs to investigate the role of the EGFR ligand heparin binding-epidermal growth factor (HB-EGF) in ET-1-induced transactivation of EGFR, intracellular calcium mobilization, and VSMCs contraction. While baseline blood pressures were similar in HB-EGF-deficient and in wild-type littermate mice, the vasoconstrictor actions of ET-1 were attenuated in HB-EGF–/– animals. In isolated mouse carotid artery segments mounted in an arteriograph, ET-1 caused only a weak increase in isovolumetric tone in HB-EGF-deficient vessels, and this effect was mimicked by inhibition of EGFR tyrosine kinase or phosphoinositide 3-kinase (PI3K) in wild-type arteries with or without endothelium, indicating a specific role in VSMCs. EGFR or PI3K inhibitors had no effect on KCl-induced contraction, which was normal in HB-EGF-deficient mice. To confirm that the abnormal responses in HB-EGF-deficient mice were due to impaired EGFR signaling, we studied VSMCs from waved-2 (wa2) mice; these animals have a mutation causing a partial loss of function of EGFR tyrosine kinase activity. The ET-1-induced calcium peak was reduced by 30% in VSMCs from wa2 mice and from HB-EGF–/– mice. This effect was reproduced by preincubation of wild-type VSMCs with EGFR inhibitor AG1478 and PI3K inhibitors LY294002 and wortmannin. ProHB-EGF is bound to the cell membrane and released after cleavage by metalloproteinases; its action may contribute to effects of GPCR agonists on cell growth. Pretreatment of mouse VSMCs with batimastat, a metalloproteinase inhibitor, significantly attenuated ET-1-induced [Ca²⁺]_i response in wild-type cells. Human proHB-EGF has been shown to be the endogenous receptor for Corynebacterium diphteriae toxin (DT). Mutated DT toxin (CRM197) is devoid of toxicity but it neutralizes HB-EGF binding to EGFR. Pretreatment of human VSMCs from internal mammary arteries with CRM197 significantly blunted ET-1-stimulated calcium transients. In conclusion, these findings suggest that the mechanism of ET-1-induced vasoconstriction involves HB-EGF-mediated transactivation of the EGFR. This functional cascade requires modulation of agonist-induced calcium transient by EGFR and PI3K with extremely fast kinetics, suggesting a novel paradigm for GPCR-mediated calcium signaling, which may offer future therapeutic targets.—Chansel, D., Ciroldi, M., Vandermeersch, S., Jackson, L. F., Gomez, A-M., Henrion, D., Lee, D. C., Coffman, T. M., Richard, S., Dussaule, J-C., Tharaux, P-L., Heparin binding EGF is necessary for vasospastic response to endothelin.

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