Get access

Nitric Oxide-Induced Changes in Endothelial Expression of Phosphodiesterases 2, 3, and 5

Authors

  • Christoph J. Schankin MD,

    Search for more papers by this author
    • *

      These authors contributed equally to the work.

  • Lars S. Kruse MSc, PhD,

    Search for more papers by this author
    • *

      These authors contributed equally to the work.

  • Veronika M. Reinisch MD,

    1. From the Department of Neurology, University of Munich Hospital – Großhadern, Munich, Germany (C.J. Schankin, V.M. Reinisch, S. Jungmann, U. Ferrari, and A. Straube); Department of Neurosurgery, University of Munich Hospital – Großhadern, Munich, Germany (S. Grau and R. Goldbrunner); Department of Forensic Medicine, University of Munich, Munich, Germany (I. Sinicina); Danish Headache Center, Department of Neurology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark (L.S. Kruse, J.C. Kristensen, and C. Kruuse).
    Search for more papers by this author
  • Steffen Jungmann MD,

    1. From the Department of Neurology, University of Munich Hospital – Großhadern, Munich, Germany (C.J. Schankin, V.M. Reinisch, S. Jungmann, U. Ferrari, and A. Straube); Department of Neurosurgery, University of Munich Hospital – Großhadern, Munich, Germany (S. Grau and R. Goldbrunner); Department of Forensic Medicine, University of Munich, Munich, Germany (I. Sinicina); Danish Headache Center, Department of Neurology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark (L.S. Kruse, J.C. Kristensen, and C. Kruuse).
    Search for more papers by this author
  • Julie C. Kristensen MSc,

    1. From the Department of Neurology, University of Munich Hospital – Großhadern, Munich, Germany (C.J. Schankin, V.M. Reinisch, S. Jungmann, U. Ferrari, and A. Straube); Department of Neurosurgery, University of Munich Hospital – Großhadern, Munich, Germany (S. Grau and R. Goldbrunner); Department of Forensic Medicine, University of Munich, Munich, Germany (I. Sinicina); Danish Headache Center, Department of Neurology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark (L.S. Kruse, J.C. Kristensen, and C. Kruuse).
    Search for more papers by this author
  • Stefan Grau MD,

    1. From the Department of Neurology, University of Munich Hospital – Großhadern, Munich, Germany (C.J. Schankin, V.M. Reinisch, S. Jungmann, U. Ferrari, and A. Straube); Department of Neurosurgery, University of Munich Hospital – Großhadern, Munich, Germany (S. Grau and R. Goldbrunner); Department of Forensic Medicine, University of Munich, Munich, Germany (I. Sinicina); Danish Headache Center, Department of Neurology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark (L.S. Kruse, J.C. Kristensen, and C. Kruuse).
    Search for more papers by this author
  • Uta Ferrari MD,

    1. From the Department of Neurology, University of Munich Hospital – Großhadern, Munich, Germany (C.J. Schankin, V.M. Reinisch, S. Jungmann, U. Ferrari, and A. Straube); Department of Neurosurgery, University of Munich Hospital – Großhadern, Munich, Germany (S. Grau and R. Goldbrunner); Department of Forensic Medicine, University of Munich, Munich, Germany (I. Sinicina); Danish Headache Center, Department of Neurology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark (L.S. Kruse, J.C. Kristensen, and C. Kruuse).
    Search for more papers by this author
  • Inga Sinicina MD,

    1. From the Department of Neurology, University of Munich Hospital – Großhadern, Munich, Germany (C.J. Schankin, V.M. Reinisch, S. Jungmann, U. Ferrari, and A. Straube); Department of Neurosurgery, University of Munich Hospital – Großhadern, Munich, Germany (S. Grau and R. Goldbrunner); Department of Forensic Medicine, University of Munich, Munich, Germany (I. Sinicina); Danish Headache Center, Department of Neurology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark (L.S. Kruse, J.C. Kristensen, and C. Kruuse).
    Search for more papers by this author
  • Roland Goldbrunner MD,

    1. From the Department of Neurology, University of Munich Hospital – Großhadern, Munich, Germany (C.J. Schankin, V.M. Reinisch, S. Jungmann, U. Ferrari, and A. Straube); Department of Neurosurgery, University of Munich Hospital – Großhadern, Munich, Germany (S. Grau and R. Goldbrunner); Department of Forensic Medicine, University of Munich, Munich, Germany (I. Sinicina); Danish Headache Center, Department of Neurology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark (L.S. Kruse, J.C. Kristensen, and C. Kruuse).
    Search for more papers by this author
  • Andreas Straube MD,

    1. From the Department of Neurology, University of Munich Hospital – Großhadern, Munich, Germany (C.J. Schankin, V.M. Reinisch, S. Jungmann, U. Ferrari, and A. Straube); Department of Neurosurgery, University of Munich Hospital – Großhadern, Munich, Germany (S. Grau and R. Goldbrunner); Department of Forensic Medicine, University of Munich, Munich, Germany (I. Sinicina); Danish Headache Center, Department of Neurology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark (L.S. Kruse, J.C. Kristensen, and C. Kruuse).
    Search for more papers by this author
  • Christina Kruuse MD, PhD

    1. From the Department of Neurology, University of Munich Hospital – Großhadern, Munich, Germany (C.J. Schankin, V.M. Reinisch, S. Jungmann, U. Ferrari, and A. Straube); Department of Neurosurgery, University of Munich Hospital – Großhadern, Munich, Germany (S. Grau and R. Goldbrunner); Department of Forensic Medicine, University of Munich, Munich, Germany (I. Sinicina); Danish Headache Center, Department of Neurology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark (L.S. Kruse, J.C. Kristensen, and C. Kruuse).
    Search for more papers by this author

  • Financial support: A.S.: Federal Ministry of Education and Research, Germany (BMBF, Chronic headache, project D1); C.J.S.: Förderprogramm für Forschung und Lehre (FöFoLe, reg.-no. 561) of the University of Munich; U.F.: German society for migraine and headache, Germany (DMKG, Junior Grant); L.S.K.: The Augustinus Foundation, Denmark; L.S.K. and J.C.K.: The Lundbeck Foundation, Denmark (The Lundbeck Foundation Center for Neurovascular Signaling, LUCENS); L.S.K.: The Aase and Ejnar Danielsens Foundation; C.K.: The Danish Medical Research Council.

  • Conflict of Interest: None

C.J. Schankin, University of Munich Hospital – Großhadern, Department of Neurology, Marchioninistr. 15, D-81377 Munich, Germany.

Abstract

(Headache 2010;50:431-441)

Objective.— To investigate nitric oxide (NO)-mediated changes in expression of cyclic nucleotide degrading phosphodiesterases 2A (PDE2A), PDE3B, and PDE5A in human endothelial cells.

Background.— Nitric oxide induces production of cyclic guanosine monophosphate (cGMP), which along with cyclic adenosine monophosphate (cAMP) is degraded by PDEs. NO donors and selective inhibitors of PDE3 and PDE5 induce migraine-like headache and play a role in endothelial dysfunction during stroke. The current study investigates possible NO modulation of cGMP-related PDEs relevant to headache induction in a cell line containing such PDEs.

Methods.— Real time polymerase chain reaction and Western blots were used to show expression of PDE2A, PDE3B, and PDE5A in a stable cell line of human brain microvascular endothelial cells. Effects of NO on PDE expression were analyzed at specific time intervals after continued DETA NONOate administration.

Results.— This study shows the expression of PDE2A, PDE3B, and PDE5A mRNA and PDE3B and PDE5A protein in human cerebral endothelial cells. Long-term DETA NONOate administration induced an immediate mRNA up-regulation of PDE5A (1.9-fold, 0.5 hour), an early peak of PDE2A (1.4-fold, 1 and 2 hours) and later up-regulation of both PDE3B (1.6-fold, 4 hours) and PDE2A (1.7-fold, 8 hours and 1.2-fold after 24 hours). Such changes were, however, not translated into significant changes in protein expression indicating few, if any, functional effects.

Conclusions.— Long-term NO stimulation modulated PDE3 and PDE5 mRNA expression in endothelial cells. However, PDE3 and PDE5 protein levels were unaffected by NO. The presence of PDE3 or PDE5 in endothelial cells indicates that selective inhibitors may have functional effects in such cells. A complex interaction of cGMP and cAMP in response to NO administration may take place if the mRNA translates into active protein. Whether or not this plays a role in the headache mechanisms remains to be investigated.

Get access to the full text of this article

Ancillary