The Journal of Experimental Medicine
Janeway's Immunobiology 7th Edition
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Published online 15 May 2006 doi:10.1084/jem.20060375
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 6, 1447-1458
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ARTICLE

 Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality

Kiichiro Yano1, Patricia C. Liaw3, Janet M. Mullington2, Shu-Ching Shih1, Hitomi Okada1, Natalya Bodyak1, Peter M. Kang1, Lisa Toltl3, Bryan Belikoff1, Jon Buras1, Benjamin T. Simms4, Joseph P. Mizgerd4, Peter Carmeliet5, S. Ananth Karumanchi1, and William C. Aird1

1 Center for Vascular Biology Research, Division of Molecular and Vascular Medicine, and 2 Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215
3 Department of Medicine, McMaster University, Henderson Research Centre, Hamilton, Ontario L8V 1C3, Canada
4 Physiology Program, Harvard School of Public Health, Boston, MA 02115
5 The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, 3000 Leuven, Belgium

CORRESPONDENCE William C. Aird: waird{at}bidmc.harvard.edu

Sepsis, the systemic inflammatory response to infection, is a leading cause of morbidity and mortality. The mechanisms of sepsis pathophysiology remain obscure but are likely to involve a complex interplay between mediators of the inflammatory and coagulation pathways. An improved understanding of these mechanisms should provide an important foundation for developing novel therapies. In this study, we show that sepsis is associated with a time-dependent increase in circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in animal and human models of sepsis. Adenovirus-mediated overexpression of soluble Flt-1 (sFlt-1) in a mouse model of endotoxemia attenuated the rise in VEGF and PlGF levels and blocked the effect of endotoxemia on cardiac function, vascular permeability, and mortality. Similarly, in a cecal ligation puncture (CLP) model, adenovirus–sFlt-1 protected against cardiac dysfunction and mortality. When administered in a therapeutic regimen beginning 1 h after the onset of endotoxemia or CLP, sFlt peptide resulted in marked improvement in cardiac physiology and survival. Systemic administration of antibodies against the transmembrane receptor Flk-1 but not Flt-1 protected against sepsis mortality. Adenovirus-mediated overexpression of VEGF but not PlGF exacerbated the lipopolysaccharide-mediated toxic effects. Together, these data support a pathophysiological role for VEGF in mediating the sepsis phenotype.

Abbreviations used: CLP, cecal ligation puncture; HUVEC, human umbilical vein endothelial cell; ICAM-1, intercellular adhesion molecule 1; PlGF, placental growth factor; sFlt, soluble Flt; TNFR, TNF receptor; VCAM-1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor.


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