Transient mechanoactivation of neutral sphingomyelinase in caveolae to generate ceramide.
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.
Czarny
Malgorzata
M
Sidney Kimmel Cancer Center, Division of Vascular Biology and Angiogenesis, San Diego, California 92121, USA.
Liu
Jun
J
Oh
Phil
P
Schnitzer
Jan E
JE
D000818:Animals; D021941:Caveolae / Q000201:enzymology / Q000502:physiology*; D002518:Ceramides / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000201:enzymology / Q000502:physiology* / Q000648:ultrastructure; D004789:Enzyme Activation / Q000502:physiology; D006439:Hemodynamics; D020935:MAP Kinase Signaling System; D008465:Mechanoreceptors / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013314:Stress, Mechanical; D013997:Time Factors
D002518:Ceramides; D013108:Sphingomyelin Phosphodiesterase