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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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Effect of PlGF deficiency on tissue and/or circulating levels of PlGF, VEGF, sFlt-1, and IL-6. (A, a–d) PLGF+/+ (WT) or PLGF−/− (KO) male mice were injected i.p. with or without 16 mg/kg LPS. Blood samples were taken 24 h later and assayed for plasma levels of free PlGF, free VEGF, sFlt-1, and IL-6. (e–h) Same as in a–d, except that wild-type mice were pretreated with anti-PlGF antibody (Pab) or IgG (CTL) and injected i.p. with or without 16 mg/kg LPS. (B) PLGF+/+ (WT) or PLGF−/− male mice were injected i.p. with or without 16 mg/kg LPS. Mouse organs were assayed for VEGF protein levels by ELISA at the time points indicated. Data are expressed as means + SD of three independent experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.0001 compared with the respective untreated controls (and where indicated between LPS-treated PlGF-deficient and wild-type mice).
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fig2: Effect of PlGF deficiency on tissue and/or circulating levels of PlGF, VEGF, sFlt-1, and IL-6. (A, a–d) PLGF+/+ (WT) or PLGF−/− (KO) male mice were injected i.p. with or without 16 mg/kg LPS. Blood samples were taken 24 h later and assayed for plasma levels of free PlGF, free VEGF, sFlt-1, and IL-6. (e–h) Same as in a–d, except that wild-type mice were pretreated with anti-PlGF antibody (Pab) or IgG (CTL) and injected i.p. with or without 16 mg/kg LPS. (B) PLGF+/+ (WT) or PLGF−/− male mice were injected i.p. with or without 16 mg/kg LPS. Mouse organs were assayed for VEGF protein levels by ELISA at the time points indicated. Data are expressed as means + SD of three independent experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.0001 compared with the respective untreated controls (and where indicated between LPS-treated PlGF-deficient and wild-type mice).

Mentions: We next wished to determine whether PlGF contributes to sepsis outcome. To that end, 10–12-wk-old PlGF−/− mice or wild-type littermates were administered 18 mg/kg LPS or subjected to CLP. PlGF deficiency was associated with significantly lower survival rate in both the endotoxemia model (wild-type male, 62.5% vs. PlGF−/− male, 11.8%; wild-type female, 56.3% vs. PlGF−/− female, 12.5%) and in CLP (wild-type male, 50% vs. PlGF−/− male, 0%; wild-type female, 50% vs. PlGF−/− female, 0%; Fig. 1 D). The differences in survival between wild-type male and female FVB mice were not statistically significant. Interestingly, the increased mortality associated with the genetic deficiency of PlGF was less pronounced in younger mice (6 wk old; unpublished data). To test for the effect of acute PlGF down-regulation in the adult animal, FVB mice were administered 1 mg of neutralizing monoclonal anti-PlGF antibody (clone 5D11D4) i.p. 20 h before initiation of sepsis. In these experiments, PlGF levels in the plasma were undetectable (see Fig. 2 A). In 10–12-wk-old male mice, anti-PlGF antibody–mediated depletion of PlGF resulted in reduced sepsis survival in LPS-treated mice (control IgG, 62.5% vs. PlGF antibody, 12.5%) and mice subjected to CLP (control IgG, 50% vs. PlGF antibody, 0%; Fig. 1 D). Similar results were obtained in female mice and in younger animals (6 wk old; unpublished data). Thus, PlGF has a protective role in sepsis.


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)

Effect of PlGF deficiency on tissue and/or circulating levels of PlGF, VEGF, sFlt-1, and IL-6. (A, a–d) PLGF+/+ (WT) or PLGF−/− (KO) male mice were injected i.p. with or without 16 mg/kg LPS. Blood samples were taken 24 h later and assayed for plasma levels of free PlGF, free VEGF, sFlt-1, and IL-6. (e–h) Same as in a–d, except that wild-type mice were pretreated with anti-PlGF antibody (Pab) or IgG (CTL) and injected i.p. with or without 16 mg/kg LPS. (B) PLGF+/+ (WT) or PLGF−/− male mice were injected i.p. with or without 16 mg/kg LPS. Mouse organs were assayed for VEGF protein levels by ELISA at the time points indicated. Data are expressed as means + SD of three independent experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.0001 compared with the respective untreated controls (and where indicated between LPS-treated PlGF-deficient and wild-type mice).
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fig2: Effect of PlGF deficiency on tissue and/or circulating levels of PlGF, VEGF, sFlt-1, and IL-6. (A, a–d) PLGF+/+ (WT) or PLGF−/− (KO) male mice were injected i.p. with or without 16 mg/kg LPS. Blood samples were taken 24 h later and assayed for plasma levels of free PlGF, free VEGF, sFlt-1, and IL-6. (e–h) Same as in a–d, except that wild-type mice were pretreated with anti-PlGF antibody (Pab) or IgG (CTL) and injected i.p. with or without 16 mg/kg LPS. (B) PLGF+/+ (WT) or PLGF−/− male mice were injected i.p. with or without 16 mg/kg LPS. Mouse organs were assayed for VEGF protein levels by ELISA at the time points indicated. Data are expressed as means + SD of three independent experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.0001 compared with the respective untreated controls (and where indicated between LPS-treated PlGF-deficient and wild-type mice).
Mentions: We next wished to determine whether PlGF contributes to sepsis outcome. To that end, 10–12-wk-old PlGF−/− mice or wild-type littermates were administered 18 mg/kg LPS or subjected to CLP. PlGF deficiency was associated with significantly lower survival rate in both the endotoxemia model (wild-type male, 62.5% vs. PlGF−/− male, 11.8%; wild-type female, 56.3% vs. PlGF−/− female, 12.5%) and in CLP (wild-type male, 50% vs. PlGF−/− male, 0%; wild-type female, 50% vs. PlGF−/− female, 0%; Fig. 1 D). The differences in survival between wild-type male and female FVB mice were not statistically significant. Interestingly, the increased mortality associated with the genetic deficiency of PlGF was less pronounced in younger mice (6 wk old; unpublished data). To test for the effect of acute PlGF down-regulation in the adult animal, FVB mice were administered 1 mg of neutralizing monoclonal anti-PlGF antibody (clone 5D11D4) i.p. 20 h before initiation of sepsis. In these experiments, PlGF levels in the plasma were undetectable (see Fig. 2 A). In 10–12-wk-old male mice, anti-PlGF antibody–mediated depletion of PlGF resulted in reduced sepsis survival in LPS-treated mice (control IgG, 62.5% vs. PlGF antibody, 12.5%) and mice subjected to CLP (control IgG, 50% vs. PlGF antibody, 0%; Fig. 1 D). Similar results were obtained in female mice and in younger animals (6 wk old; unpublished data). Thus, PlGF has a protective role in sepsis.

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