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Elevated levels of placental growth factor represent an adaptive host response in sepsis.

Yano K, Okada Y, Beldi G, Shih SC, Bodyak N, Okada H, Kang PM, Luscinskas W, Robson SC, Carmeliet P, Karumanchi SA, Aird WC - J. Exp. Med. (2008)

Bottom Line: Belikoff, J.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.

View Article: PubMed Central - PubMed

Affiliation: The Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.

ABSTRACT
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.

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Additional survival studies in mouse models of sepsis. Male PLGF+/+ (WT) or PLGF−/− mice were injected with Ad overexpressing GFP (GFP-ad) or PlGF (PlGF-ad; A), VEGF (VEGF-ad; B), or sFlt-1 (sFlt-ad; C). 3 d later, the animals were administered saline (control) or LPS i.p. and monitored for survival.
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fig6: Additional survival studies in mouse models of sepsis. Male PLGF+/+ (WT) or PLGF−/− mice were injected with Ad overexpressing GFP (GFP-ad) or PlGF (PlGF-ad; A), VEGF (VEGF-ad; B), or sFlt-1 (sFlt-ad; C). 3 d later, the animals were administered saline (control) or LPS i.p. and monitored for survival.

Mentions: The increased mortality in endotoxemic PlGF−/− mice was rescued by overexpression of PlGF (Fig. 6 A). However, the elevated circulating levels of PlGF in the PlGF-adenovirus (Ad)–treated mice (5,823.4 ± 833.6 pg/ml) did not confer a survival advantage over GFP-Ad (control)–injected wild-type animals. To determine whether PlGF deficiency rendered animals more sensitive to the effects of VEGF, mice were injected with control virus or VEGF-Ad and administered small doses of LPS (14 mg/kg). At the latter dose, 93.8% of wild-type and PlGF−/− mice survived (Fig. 6 B). However, overexpression of VEGF (plasma levels, 4,204.5 ± 901.8 pg/ml) resulted in a marked increased in mortality in PlGF−/− compared with wild-type animals (wild-type, 50% vs. PlGF−/−, 100%) (Fig. 6 B). Finally, the increased mortality associated with PlGF deficiency was reversed by overexpression of sFlt-1 (Fig. 6 C). Collectively, these results suggest that elevated VEGF levels are both sufficient and necessary to promote sepsis mortality in PlGF-deficient mice.


Elevated levels of placental growth factor represent an adaptive host response in sepsis.

Yano K, Okada Y, Beldi G, Shih SC, Bodyak N, Okada H, Kang PM, Luscinskas W, Robson SC, Carmeliet P, Karumanchi SA, Aird WC - J. Exp. Med. (2008)

Additional survival studies in mouse models of sepsis. Male PLGF+/+ (WT) or PLGF−/− mice were injected with Ad overexpressing GFP (GFP-ad) or PlGF (PlGF-ad; A), VEGF (VEGF-ad; B), or sFlt-1 (sFlt-ad; C). 3 d later, the animals were administered saline (control) or LPS i.p. and monitored for survival.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2571936&req=5

fig6: Additional survival studies in mouse models of sepsis. Male PLGF+/+ (WT) or PLGF−/− mice were injected with Ad overexpressing GFP (GFP-ad) or PlGF (PlGF-ad; A), VEGF (VEGF-ad; B), or sFlt-1 (sFlt-ad; C). 3 d later, the animals were administered saline (control) or LPS i.p. and monitored for survival.
Mentions: The increased mortality in endotoxemic PlGF−/− mice was rescued by overexpression of PlGF (Fig. 6 A). However, the elevated circulating levels of PlGF in the PlGF-adenovirus (Ad)–treated mice (5,823.4 ± 833.6 pg/ml) did not confer a survival advantage over GFP-Ad (control)–injected wild-type animals. To determine whether PlGF deficiency rendered animals more sensitive to the effects of VEGF, mice were injected with control virus or VEGF-Ad and administered small doses of LPS (14 mg/kg). At the latter dose, 93.8% of wild-type and PlGF−/− mice survived (Fig. 6 B). However, overexpression of VEGF (plasma levels, 4,204.5 ± 901.8 pg/ml) resulted in a marked increased in mortality in PlGF−/− compared with wild-type animals (wild-type, 50% vs. PlGF−/−, 100%) (Fig. 6 B). Finally, the increased mortality associated with PlGF deficiency was reversed by overexpression of sFlt-1 (Fig. 6 C). Collectively, these results suggest that elevated VEGF levels are both sufficient and necessary to promote sepsis mortality in PlGF-deficient mice.

Bottom Line: Belikoff, J.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.

View Article: PubMed Central - PubMed

Affiliation: The Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus