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Transient mechanoactivation of neutral sphingomyelinase in caveolae to generate ceramide.

Authors: Czarny, M  Liu, J  Oh, P  Schnitzer, JE 
Citation: Czarny M, etal., J Biol Chem. 2003 Feb 14;278(7):4424-30. Epub 2002 Dec 6.
Pubmed: (View Article at PubMed) PMID:12473648
DOI: Full-text: DOI:10.1074/jbc.M210375200

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.


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CRRD Object Information
CRRD ID: 1581395
Created: 2006-10-02
Species: All species
Last Modified: 2006-10-02
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.