Elevated levels of placental growth factor represent an adaptive host response in sepsis.
Recently, we demonstrated that circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are increased in sepsis (Yano, K., P.C. Liaw, J.M. Mullington, S.C. Shih, H. Okada, N. Bodyak, P.M. Kang, L. Toltl, B. Belikoff, J. Buras, et al. 2006. J. Exp. Med. 203:1447-1458). Moreover, enhanced VEGF/Flk-1 signaling was shown to contribute to sepsis morbidity and mortality. We tested the hypothesis that PlGF also contributes to sepsis outcome. In mouse models of endotoxemia and cecal ligation puncture, the genetic absence of PlGF or the systemic administration of neutralizing anti-PlGF antibodies resulted in higher mortality compared with wild-type or immunoglobulin G-injected controls, respectively. The increased mortality associated with genetic deficiency of PlGF was reversed by adenovirus (Ad)-mediated overexpression of PlGF. In the endotoxemia model, PlGF deficiency was associated with elevated circulating levels of VEGF, induction of VEGF expression in the liver, impaired cardiac function, and organ-specific accentuation of barrier dysfunction and inflammation. Mortality of endotoxemic PlGF-deficient mice was increased by Ad-mediated overexpression of VEGF and was blocked by expression of soluble Flt-1. Collectively, these data suggest that up-regulation of PlGF in sepsis is an adaptive host response that exerts its benefit, at least in part, by attenuating VEGF signaling.
The Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Kiichiro
K
Yano
Yoshiaki
Y
Okada
Guido
G
Beldi
Shou-Ching
SC
Shih
Natalya
N
Bodyak
Hitomi
H
Okada
Peter M
PM
Kang
William
W
Luscinskas
Simon C
SC
Robson
Peter
P
Carmeliet
S Ananth
SA
Karumanchi
William C
WC
Aird
D000704:Analysis of Variance; D000818:Animals; D005786:Gene Expression Regulation / Q000276:immunology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018805:Sepsis / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor