Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality.
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.
Yano
Kiichiro
K
Center for Vascular Biology Research, Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Liaw
Patricia C
PC
Mullington
Janet M
JM
Shih
Shu-Ching
SC
Okada
Hitomi
H
Bodyak
Natalya
N
Kang
Peter M
PM
Toltl
Lisa
L
Belikoff
Bryan
B
Buras
Jon
J
Simms
Benjamin T
BT
Mizgerd
Joseph P
JP
Carmeliet
Peter
P
Karumanchi
S Ananth
SA
Aird
William C
WC
D000818:Animals; D002432:Cecum / Q000382:microbiology; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000097:blood; D006801:Humans; D007249:Inflammation / Q000097:blood; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000097:blood; D018805:Sepsis / Q000097:blood* / Q000401:mortality; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*
D008070:Lipopolysaccharides; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor