Vascular barrier regulation by PAF, ceramide, caveolae, and NO - an intricate signaling network with discrepant effects in the pulmonary and systemic vasculature.
Increased endothelial permeability and vascular barrier failure are hallmarks of inflammatory responses in both the pulmonary and the systemic circulation. Platelet-activating factor (PAF) has been implicated as an important lipid mediator in the formation of pulmonary and extrapulmonary edema. Ostensibly, the PAF-induced signaling pathways in endothelial cells utilize similar structures and molecules including acid sphingomyelinase, ceramide, caveolae, endothelial nitric oxide synthase, and nitric oxide, in pulmonary and systemic microvessels. Yet, the constituents of these signaling pathways act and respond in distinctly different and frequently opposing ways in the lung versus organs of the systemic circulation. By confronting seemingly discrepant findings from the literature, we reconstruct the differential signaling pathways by which PAF regulates edema formation in the systemic and the pulmonary vascular bed, and trace this dichotomy from the level of myosin light chain kinase via the regulation of endothelial nitric oxide synthase and sphingomyelinase signaling to the level of caveolar trafficking. Here, we propose that PAF regulates vascular barrier function in individual organs by opposing signaling pathways that culminate in increased respectively decreased nitric oxide synthesis in the systemic and the pulmonary endothelium. The present review may provide a physiological explanation for the overall disappointing results of previous pharmacological strategies in conditions of generalized barrier failure such as sepsis, and instead advertises the development of organ-specific interventions by targeting the individual composition or trafficking of endothelial caveolae.
Kuebler
Wolfgang M
WM
The Keenan Research Center at the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Canada.
Yang
Yang
Y
Samapati
Rudi
R
Uhlig
Stefan
S
D002199:Capillary Permeability; D021941:Caveolae / Q000378:metabolism* / Q000502:physiology; D002463:Cell Membrane Permeability; D002518:Ceramides / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010972:Platelet Activating Factor / Q000378:metabolism*; D011652:Pulmonary Circulation; D015398:Signal Transduction
D002518:Ceramides; D010972:Platelet Activating Factor; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III