not until the nineteenth century was it generally agreed that arteries and veins are connected by capillaries and that these capillaries indeed have a cellular wall , the socalled endothelium . at this point in time , one was convinced that the endothelium was a passive inner layer of blood vessels , not participating in any kind of active processes . nowadays , better understanding of physiological processes involving the endothelium ( for example , coagulation , hemostasis , and so forth ) has led to appreciation of the endothelium as in independent and active organ system . during the past decade , endothelial injury has attracted much attention - being a crucial event in the pathogenesis of experimental septic organ dysfunction . as a consequence , several circulating factors released by the activated endothelial cells , neighboring support cells ( such as vascular smooth muscle cells and pericytes ) , or platelets have been identified as biomarkers of outcome in sepsis . in the previous issue of critical care , mankhambo and colleagues report on circulating levels of vascular endothelial growth factor ( vegf ) , platelet - derived growth factor , fibroblast growth factor , angiopoietin ( ang)-1 and ang-2 in malawian children with severe infection . they found robust increases in vegf , platelet - derived growth factor , fibroblast growth factor and ang-2 levels ( twofold to ninefold ) , whereas ang-1 was modestly decreased by only 15% ( not significant ) . survivors had lower ang-2 and higher platelet - derived growth factor and ang-1 levels , respectively ( figure 1 ) . only ( low ) schematic model of the main findings for circulating levels of vascular endothelial growth factor ( vegf ) , platelet - derived growth factor ( pdgf ) , fibroblast growth factor ( fgf ) , angiopoietin ( ang)-1 and ang-2 in malawian children with severe infection from the study by mankhambo and colleagues . the ang / tie2 ligand - receptor system was discovered as the second class of vascular - specific receptor tyrosine kinases ( the first being the vegf / vegfreceptor system ) . classically thought of as an important regulator in vessel maturation and remodeling , recent studies demonstrated that the ang / tie2 system not only regulates angiogenesis but also controls endothelial inflammation in a nonredundant manner . ang-1 and ang-2 are antagonistic ligands that bind to the extracellular domain of the tie2 receptor , which is almost exclusively expressed by endothelial cells . binding of the agonist ang-1 maintains vessel integrity , inhibits vascular leakage , suppresses inflammatory gene expression , and prevents recruitment and transmigration of leukocytes . in contrast , binding of ang-2 to tie2 disrupts protective ang-1 signaling and facilitates endothelial inflammation , most probably via preventing ang-1 from phosphorylating tie2 . ang-2 was identified recently as a strong and independent predictor of outcome in early and later stages of critical illness in adults [ 5 - 9 ] . giuliano and coworkers were the first to report that ang-2 levels were significantly elevated and ang-1 levels were significantly decreased in children with septic shock compared to children with either systemic inflammatory response syndrome or sepsis . only circulating ang-2 , however , correlated with disease severity and outcome . they identified a close correlation of ang-2 with surrogate markers of capillary leakage and found a relevant role of ang-2 in predicting the intensive care unit length of stay . in contrast to septic children of the aforementioned study , circulating ang-1 levels were normal or even elevated after cardiopulmonary bypass . finally , recent data coming from ugandan children indicate that ang-2 might serve as a biomarker to discriminate uncomplicated malaria from cerebral malaria . while the mediator function of both ang-1 and ang-2 has been well established in preclinical research , only ang-2 has been established as a clinically useful biomarker in the critical care arena . speculation is tempting , however , on the disturbances in the ang / tie2 system during sepsis being a shift from the more protective ang-1 to the more vascular disruptive ang-2 . while some authors found elevated ang-1 levels , others detected low ang-1 concentrations in intensive care unit patients . this finding might be explained by differences in the samples used for analysis . unlike ang-2 , which is exclusively stored in endothelial cells , ang-1 is not exclusively expressed by the vascular wall ( figure 1 ) - a high amount of ang-1 ( and vegf ) is also found in platelets . false positive ang-1 levels can therefore result from the ex vivo activation of platelets within serum tubes , a problem recognized only recently . the article by mankhambo and colleagues adds knowledge to our current understanding of ang-1 in critical illness . plasma ang-1 levels were not different between patients and controls , but low ang-1 was independently associated with poor prognosis . therefore it is reasonable to assume that a very small decrease in circulating ang-1 has a huge impact on outcome , and that low ang-1 is probably not associated with mortality in a linear fashion . one might speculate that low ang-1 per se represents an important risk factor for adverse out come in children with sepsis . unfortunately , the authors neither investigated the correlation between plasma ang-1 and clinicopathologic features of multiorgan dysfunction syndrome , nor reported the sensitivity and specificity of specific ang-1 cut - off values in predicting outcome . with regard to the value of circulating ang-1 as a biomarker in sepsis what is the role of ang-1 in platelets and does platelet - derived ang-1 correlate with outcome ? is it possible to quantify ang-1 in a compartment - specific fashion ( that is , true circulating ang-1 vs. platelet - derived ang-1 ) ? is there a specific all - or - nothing cut - off value for ang-1 , or is the ratio between ang-1 and ang-2 critical for outcome prediction ? all of these questions remain an active focus in several laboratories , including our own .
endothelial injury has emerged as a crucial early event in the pathogenesis of microcirculatory dysfunction , capillary leakage and multiorgan dysfunction syndrome . 
 the endothelial - specific angiopoietin ( ang)/tie2 ligand - receptor system has been identified recently as a nonredundant regulator of endothelial responsiveness . 
 ang-1 is a tie2 agonist and promotes endothelial stabilization and quiescence , whereas ang-2 is a tie2 antagonist and promotes endothelial activation , destabilization , and inflammation . while the mediator function of both ang-1 and 
 ang-2 has been well established in preclinical research , only ang-2 has been identified as a clinically useful biomarker in the critical care arena . in the previous issue of critical care , mankhambo and 
 colleagues report on angiogenic factors in malawian children with severe bacterial infection . among those children , diminished levels of the vessel - protective factor 
 ang-1 remained a significant predictor of outcome after multivariate adjustment . 
 whether low ang-1 represents an important risk factor of adverse outcome in critically ill adults remains to be seen .