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Originally published In Press as doi:10.1074/jbc.M210375200 on December 6, 2002

J. Biol. Chem., Vol. 278, Issue 7, 4424-4430, February 14, 2003
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Transient Mechanoactivation of Neutral Sphingomyelinase in Caveolae to Generate Ceramide*

Malgorzata CzarnyDagger , Jun LiuDagger §, Phil Oh, and Jan E. Schnitzer

From the Sidney Kimmel Cancer Center, Division of Vascular Biology and Angiogenesis, San Diego, California 92121

The vascular endothelium acutely autoregulates blood flow in vivo in part through unknown mechanosensing mechanisms. Here, we report the discovery of a new acute mechanotransduction pathway. Hemodynamic stressors from increased vascular flow and pressure in situ rapidly and transiently induce the activity of neutral sphingomyelinase but not that acid sphingomyelinase in a time- and flow rate-dependent manner, followed by the generation of ceramides. This acute mechanoactivation occurs directly at the luminal endothelial cell surface primarily in caveolae enriched in sphingomyelin and neutral sphingomyelinase, but not acid sphingomyelinase. Scyphostatin, which specifically blocks neutral but not acid sphingomyelinase, inhibits mechano-induced neutral sphingomyelinase activity as well as downstream activation of extracellular signal-regulated kinase 1 and 2 (ERK1 and ERK2) by increased flow in situ. We postulate a novel physiological function for neutral sphingomyelinase as a new mechanosensor initiating the ERK cascade and possibly other mechanotransduction pathways.

* This work was supported in part by National Institutes of Health Grant HL67386 (to J. E. S.) and the Beth Israel Foundation. This work was presented in part at the annual meeting of the Federation of American Societies for Experimental Biology in San Diego, CA, April 15-18, 2000 (Liu, J., and Schnitzer, J. E. (2000) FASEB J. 14, A457 (abstr.)).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Joint first authors who contributed equally to this work.

§ Present address: Department of Physiology and Pharmacology and MBR Cancer Center, West Virginia University School of Medicine, P. O. Box 9229, Morgantown, WV 26506.

To whom correspondence should be addressed: Sidney Kimmel Cancer Center, Division of Vascular Biology and Angiogenesis, 10835 Altman Row, San Diego, CA 92121. Tel.: 619-450-5990 (ext. 320); Fax: 619-450-3251; E-mail: jschnitzer@skcc.org.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
M. Czarny and J. E. Schnitzer
Neutral sphingomyelinase inhibitor scyphostatin prevents and ceramide mimics mechanotransduction in vascular endothelium
Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1344 - H1352.
[Abstract] [Full Text] [PDF]


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