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The angiogenic factors and their soluble receptors in sepsis: friend, foe, orboth?

The endothelium represents an important source of, and a target for, inflammation insepsis. Angiogenic factors and their receptors, including vascular endothelialgrowth factor (VEGF)/VEGF receptor and the angiopoietin/Tie2 signaling pathways,have recently received great attention in critically ill patients, including thosewith sepsis [13], because of their pivotal roles in both angiogenesis and microvascularpermeability. VEGF, as the most potent proangiogenic factor, has already beenidentified as an important target for cancer therapy. Disassembly of an intactendothelial cell junction is necessary for the angiogenesis process. The endothelialbarrier-breaking properties are indeed an important part of the VEGF role in theregulation of angiogenesis. However, a high dose or prolonged duration of VEGF maylead to excessive barrier-breaking effects. The favorable results observed with theonly US Food and Drug Administration-approved anti-VEGF agent, bevacizumab, by Jeongand colleagues [4] are likely to provide potential advances for future therapeuticopportunities in sepsis.

On the contrary, VEGF shows endothelial survival signals, and suppression of VEGFsignaling inhibits endothelial survival and increases apoptosis, which in turn maycontribute to the development of sepsis-induced organ dysfunction [5]. Furthermore, other than an independent function on endothelial cells,VEGF plays an important role in mobilizing endothelial progenitor cells underpathologic conditions such as cancer and sepsis. While the decrease of circulatingendothelial progenitor cells (cEPCs) after anti-VEGF treatment is beneficial incancer, this may not be so in sepsis. The endothelium is a chief target ofsepsis-induced events, and clinical outcome in septic patients is largely dependenton the ability to reconstitute damaged endothelium. Indeed, several studies haveobserved an increase in cEPC numbers in septic patients and a correlation betweencEPC concentration and survival. The increased number of cEPCs in sepsis mighttherefore be a consequence of the body’s attempt to limit vascular damage byinducing endogenous endothelial repair mechanisms. The dramatic decrease of cEPCsaccompanied by anti-VEGF treatment may impair endothelial repair capacity and bringunfavorable effects in sepsis.

The angiogenic factors and their soluble receptors therefore do have a complex roleand seemingly play both good and bad roles during sepsis development and therapy. Acertain level of VEGF is necessary for normalizing endothelial function, andabnormally high or low levels of VEGF might shift its role from endothelialprotective to endothelial barrier disruptive. This view can also provide additionalpossible explanations for why Jeong and colleagues’ study suggests that a highdose of bevacizumab may have deleterious effects in an experimental sepsis model.Future studies on the dynamic change of the angiogenic factors, their solublereceptors and cEPC counts during and after each therapy, as well as thecontext-dependent role of them, may provide background data for using theseangiogenic factors and their soluble receptors as therapeutic targets for sepsistreatment in clinical practice.



Circulating endothelial progenitor cell


Vascular endothelial growthfactor.


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This work was supported by the National Natural Science Foundation of China(Grant No. 81071534).

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Correspondence to Yao-Qing Tang.

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The authors declare that they have no competing interests.

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Zhang, RY., Liu, YY., Qu, HP. et al. The angiogenic factors and their soluble receptors in sepsis: friend, foe, orboth?. Crit Care 17, 446 (2013).

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  • Bevacizumab
  • Septic Patient
  • Angiogenic Factor
  • Endothelial Progenitor Cell
  • Endothelial Barrier