The angiogenic factors and their soluble receptors in sepsis: friend, foe, orboth?
© BioMed Central Ltd. 2013
Published: 22 August 2013
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 [1–3], 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  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 . 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.
This work was supported by the National Natural Science Foundation of China(Grant No. 81071534).
- Yano K, Liaw PC, Mullington JM, Shih SC, Okada H, Bodyak N, Kang PM, Toltl L, Belikoff B, Buras J, Simms BT, Mizgerd JP, Carmeliet P, Karumanchi SA, Aird WC: Vascular endothelial growth factor is an important determinant of sepsismorbidity and mortality. J Exp Med 2006, 203: 1447-1458. 10.1084/jem.20060375PubMedPubMed CentralView ArticleGoogle Scholar
- Kumpers P, Lukasz A, David S, Horn R, Hafer C, Faulhaber-Walter R, Fliser D, Haller H, Kielstein JT: Excess circulating angiopoietin-2 is a strong predictor of mortality incritically ill medical patients. Crit Care 2008, 12: R147. 10.1186/cc7130PubMedPubMed CentralView ArticleGoogle Scholar
- Kumpers P, van Meurs M, David S, Molema G, Bijzet J, Lukasz A, Biertz F, Haller H, Zijlstra JG: Time course of angiopoietin-2 release during experimental human endotoxemiaand sepsis. Crit Care 2009, 13: R64. 10.1186/cc7866PubMedPubMed CentralView ArticleGoogle Scholar
- Jeong SJ, Han SH, Kim CO, Choi JY, Kim JM: Anti-vascular endothelial growth factor antibody attenuates inflammation anddecreases mortality in an experimental model of severe sepsis. Crit Care 2013, 17: R97. 10.1186/cc12742PubMedPubMed CentralView ArticleGoogle Scholar
- Jesmin S, Zaedi S, Islam AM, Sultana SN, Iwashima Y, Wada T, Yamaguchi N, Hiroe M, Gando S: Time-dependent alterations of VEGF and its signaling molecules in acute lunginjury in a rat model of sepsis. Inflammation 2012, 35: 484-500. 10.1007/s10753-011-9337-1PubMedView ArticleGoogle Scholar