Regulation of vascular permeability by sphingolipids
Final Report Abstract
Our major findings are summarized. Within minutes the PAF-induced stimulation of ASM leads to a decrease in endothelial NO production and an increase in endothelial calcium levels. The simultaneous decrease of the barrier protective NO and the increase of intracellular calcium via activation of the myosin light chain kinase leads to a sudden increase in vascular permeability. We hypothesize that the activation of the ASM and the ensuing ceramide production lead to a reorganization of caveolae that is required to assemble several proteins therein. The decreased NO production is explained by recruitment of caveolin-1 and eNOS into caveolae whose interaction keeps eNOS inactive in the membrane. The increase in endothelial calcium levels is explained by the recruitment of TRPC-channels (probably TRPC6) to caveolae. The anti-edematous eff ect of dexamethasone appears to be upstream of the activation of the ASM, off ering a novel explanation for this long known effect of steroids.
Publications
- Mechanotransduction by TRP channels: general concepts and specifi c role in the vasculature. Cell Biochem Biophys
Yin J, Kuebler WM
(See online at https://doi.org/10.1007/s12013-009-9067-2) - Sphingolipids in the lungs. Am J Respir Crit Care Med 178: 1100-1114
Uhlig S, Gulbins E
- 2008. Improved pulmonary function by acid sphingomyelinase inhibition in a newborn piglet lavage model. Am J Respir Crit Care Med 177: 1233-1241
von Wistädt BP, CF, Klemm K, Winoto-Morbach S, Uhlig U, Schütze S, Adam D, Lachmann B, Uhlig S, Krause MF
- 2009. Potent and selective inhibition of acid sphingomyelinase by bisphosphonates. Angew Chem Int Ed Engl 48: 7560-7563
Roth AG, Drescher D, Yang Y, Redmer S, Uhlig S, Arenz C
