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Cardiovascular Research Advance Access first published online on July 29, 2009
This version [Corrected Proof] published online on August 20, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp265
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

NTPDase1 (CD39) controls nucleotide-dependent vasoconstriction in mouse

Gilles Kauffenstein1, Annick Drouin2, Nathalie Thorin-Trescases2, Hélène Bachelard3, Bernard Robaye4, Pedro D'Orléans-Juste5, François Marceau1, Éric Thorin2 and Jean Sévigny1,*

1 Centre de Recherche en Rhumatologie et Immunologie, Université Laval, 2705 Boulevard Laurier, local T1-49, Québec, QC, Canada G1V 4G2
2 Institut de Cardiologie de Montréal, Université de Montréal, Montréal, QC, Canada
3 Centre de recherche sur les maladies lipidiques, Centre Hospitalier Universitaire de Québec, Université Laval, Québec, QC, Canada
4 Institut de Recherche Interdisciplinaire en Biologie humaine et moléculaire, Université Libre de Bruxelles, Gosselies, Belgium
5 Département de Pharmacologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, QC, Canada

* Corresponding author. Tel: +1 418 654 2772, Fax: +1 418 654 2765, Email: jean.sevigny{at}crchul.ulaval.ca

Aims: Extracellular nucleotides are vasoactive molecules. The concentrations of these molecules are regulated by ectonucleotidases. In this study, we investigated the role of the blood vessel ectonucleotidase NTPDase1, in the vasoconstrictor effect of nucleotides using Entpd1–/– mice.

Methods and results: Immunofluorescence, enzyme histochemistry, and HPLC analysis were used to evaluate both NTPDase expression and activity in arteries and isolated vascular smooth muscle cells (VSMCs). Vascular reactivity was evaluated in vitro and mean arterial blood pressure was recorded in anesthetized mice after nucleotide i.v. infusion. Expression of nucleotide receptors in VSMCs was determined by RT–PCR. Entpd1–/– mice displayed a dramatic deficit of nucleotidase activity in blood vessel wall in situ and in VSMCs in comparison to control mice. In aortic rings from Entpd1–/– mice, UDP and UTP induced a potent and long-lasting constriction contrasting with the weak response obtained in wild-type rings. This constriction occurred through activation of P2Y6 receptor and was independent of other uracil nucleotide-responding receptors (P2Y2 and P2Y4). UDP infusion in vivo increased blood pressure and this effect was potentiated in Entpd1–/– mice. In addition, pressurized mesenteric arteries from Entpd1–/– mice displayed an enhanced myogenic response, consistent with higher local concentrations of endogenously released nucleotides. This effect was inhibited by the P2 receptor antagonist RB-2.

Conclusion: NTPDase1 is the major enzyme regulating nucleotide metabolism at the surface of VSMCs and thus contributes to the local regulation of vascular tone by nucleotides.

KEYWORDS NTPDase1; CD39; UTP; UDP; P2Y receptor; Vasoconstriction; Myogenic tone; Smooth muscle cell

Time for primary review: 29 days


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