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(Circulation. 2003;108:342.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Sphingosine Kinase Modulates Microvascular Tone and Myogenic Responses Through Activation of RhoA/Rho Kinase

Steffen-Sebastian Bolz, MD; Lukas Vogel; Daniel Sollinger; Roland Derwand, MD; Christa Boer, PhD; Stuart M. Pitson, PhD; Sarah Spiegel, PhD; Ulrich Pohl, MD, PhD

From the Institute of Physiology, Ludwig-Maximilians-University, Munich, Germany (S.-S.B., L.V., D.S., R.D., U.P.); the Institute for Cardiovascular Research, Vrije Universiteit Medical Center, Amsterdam, the Netherlands (C.B.); the Hanson Institute, Human Immunology, Institute of Medical and Veterinary Science, Adelaide, Australia (S.M.P.); and the Department of Biochemistry, Medical College of Virginia, Virginia Commonwealth University, Richmond (S.S.).

Correspondence to Steffen-Sebastian Bolz, MD, Institute of Physiology, Ludwig Maximilians University, Schillerstrasse 44, 80336 Muenchen, Germany. E-mail bolz{at}lrz.uni-muenchen.de

Background— RhoA and Rho kinase are important modulators of microvascular tone.

Methods and Results— We tested whether sphingosine kinase (Sphk1) that generates the endogenous sphingolipid mediator sphingosine-1-phosphate (S1P) is part of a signaling cascade to activate the RhoA/Rho kinase pathway. Using a new transfection model, we report that resting tone and myogenic responses of isolated resistance arteries increased with forced expression of Sphk1 in smooth muscle cells of these arteries. Overexpression of a dominant negative Sphk1 mutant or coexpression of dominant negative mutants of RhoA or Rho kinase together with Sphk1 completely inhibited development of tone and myogenic responses.

Conclusions— The tone-increasing effects of a Sphk1 overexpression suggest that Sphk1 may play an important role in the control of peripheral resistance.

Key Words: microcirculation • muscle, smooth • arteries • genetics • vasoconstriction

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