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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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PlGF levels in sepsis and survival studies in PlGF-deficient mice. (A, a) Plasma levels of PlGF in wild-type male FVB mice injected i.p. with 18 mg/kg LPS at the time points indicated. (b) Same as in a but in a CLP mouse model. (B) Shown are results of quantitative real-time analyses (mRNA copy number per 106 copies of 18S) of PlGF in organs from male FVB mice at various time points after i.p. injection with 18 mg/kg LPS. (C) In situ hybridization (ISH) and immunohistochemistry (IHC) for PlGF in the heart, lung, and liver of male FVB mice treated in the absence (nontreated) or presence of 18 mg/kg LPS at 12 h. The insets in d, h, and i show a higher magnification of a representative area from each field. Arrows indicate PlGF signal. Bar: 50 μm; (insets) 25 μm. (D, a) Survival curves for male PLGF+/+ (wild-type, WT) or PLGF−/− (knockout, KO) mice injected i.p. with 18 mg/kg LPS. (b) Survival curves for female PLGF+/+ (WT) or PLGF−/− (KO) mice injected i.p. with 18 mg/kg LPS. (c) Survival curves for wild-type male mice pretreated with anti-PlGF antibody (PlGF ab) or IgG (CTL ab) and injected i.p. with 18 mg/kg LPS. (d) Survival curves for male PLGF+/+ (WT) or PLGF−/− (KO) mice subjected to CLP. (e) Survival curves for female PLGF+/+ (WT) or PLGF−/− (KO) mice subjected to CLP. (f) Survival curves for wild-type male mice pretreated with anti-PlGF antibody (PlGF ab) or IgG (CTL ab) and subjected to CLP. Data in A and B are expressed as means + SD of at least three independent experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.0001 compared with no treatment (0 h time point).
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fig1: PlGF levels in sepsis and survival studies in PlGF-deficient mice. (A, a) Plasma levels of PlGF in wild-type male FVB mice injected i.p. with 18 mg/kg LPS at the time points indicated. (b) Same as in a but in a CLP mouse model. (B) Shown are results of quantitative real-time analyses (mRNA copy number per 106 copies of 18S) of PlGF in organs from male FVB mice at various time points after i.p. injection with 18 mg/kg LPS. (C) In situ hybridization (ISH) and immunohistochemistry (IHC) for PlGF in the heart, lung, and liver of male FVB mice treated in the absence (nontreated) or presence of 18 mg/kg LPS at 12 h. The insets in d, h, and i show a higher magnification of a representative area from each field. Arrows indicate PlGF signal. Bar: 50 μm; (insets) 25 μm. (D, a) Survival curves for male PLGF+/+ (wild-type, WT) or PLGF−/− (knockout, KO) mice injected i.p. with 18 mg/kg LPS. (b) Survival curves for female PLGF+/+ (WT) or PLGF−/− (KO) mice injected i.p. with 18 mg/kg LPS. (c) Survival curves for wild-type male mice pretreated with anti-PlGF antibody (PlGF ab) or IgG (CTL ab) and injected i.p. with 18 mg/kg LPS. (d) Survival curves for male PLGF+/+ (WT) or PLGF−/− (KO) mice subjected to CLP. (e) Survival curves for female PLGF+/+ (WT) or PLGF−/− (KO) mice subjected to CLP. (f) Survival curves for wild-type male mice pretreated with anti-PlGF antibody (PlGF ab) or IgG (CTL ab) and subjected to CLP. Data in A and B are expressed as means + SD of at least three independent experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.0001 compared with no treatment (0 h time point).

Mentions: We recently demonstrated that circulating PlGF levels are increased in C57BL/6 mice injected with LPS or subjected to cecal ligation puncture (CLP) (7). The PlGF−/− mice used in this study were backcrossed to an FVB background. Previous studies have demonstrated strain-specific sensitivity to LPS (32–34). Thus, we wished to confirm these findings in FVB mice. The i.p. administration of 18 mg/kg LPS resulted in a time-dependent increase in plasma PlGF concentrations, with peak levels (3,447.4 pg/ml) occurring at 24 h (Fig. 1 A). Similarly, in a CLP model of sepsis, peak levels of PlGF (111.4 pg/ml) occurred at 24 h (Fig. 1 A). Previously, we demonstrated that PlGF protein levels were increased in all tissues examined, including the brain, lung, heart, liver, kidney, and spleen (7). In real-time PCR assays, there was a time-dependent induction of PlGF transcripts at 24 h in the brain (5.3-fold), lung (14.3-fold), liver (28-fold), kidney (25.7-fold), and spleen (8.5-fold). PlGF mRNA levels in the heart peaked at 6 h (54.2-fold; Fig. 1 B). In situ hybridization and immunohistochemical studies revealed a PlGF signal in perivascular cells but not the endothelium (Fig. 1 C shows the heart, lung, and liver). Collectively, these findings suggest that sepsis is associated with the widespread induction of PlGF mRNA and protein expression.


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)

PlGF levels in sepsis and survival studies in PlGF-deficient mice. (A, a) Plasma levels of PlGF in wild-type male FVB mice injected i.p. with 18 mg/kg LPS at the time points indicated. (b) Same as in a but in a CLP mouse model. (B) Shown are results of quantitative real-time analyses (mRNA copy number per 106 copies of 18S) of PlGF in organs from male FVB mice at various time points after i.p. injection with 18 mg/kg LPS. (C) In situ hybridization (ISH) and immunohistochemistry (IHC) for PlGF in the heart, lung, and liver of male FVB mice treated in the absence (nontreated) or presence of 18 mg/kg LPS at 12 h. The insets in d, h, and i show a higher magnification of a representative area from each field. Arrows indicate PlGF signal. Bar: 50 μm; (insets) 25 μm. (D, a) Survival curves for male PLGF+/+ (wild-type, WT) or PLGF−/− (knockout, KO) mice injected i.p. with 18 mg/kg LPS. (b) Survival curves for female PLGF+/+ (WT) or PLGF−/− (KO) mice injected i.p. with 18 mg/kg LPS. (c) Survival curves for wild-type male mice pretreated with anti-PlGF antibody (PlGF ab) or IgG (CTL ab) and injected i.p. with 18 mg/kg LPS. (d) Survival curves for male PLGF+/+ (WT) or PLGF−/− (KO) mice subjected to CLP. (e) Survival curves for female PLGF+/+ (WT) or PLGF−/− (KO) mice subjected to CLP. (f) Survival curves for wild-type male mice pretreated with anti-PlGF antibody (PlGF ab) or IgG (CTL ab) and subjected to CLP. Data in A and B are expressed as means + SD of at least three independent experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.0001 compared with no treatment (0 h time point).
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fig1: PlGF levels in sepsis and survival studies in PlGF-deficient mice. (A, a) Plasma levels of PlGF in wild-type male FVB mice injected i.p. with 18 mg/kg LPS at the time points indicated. (b) Same as in a but in a CLP mouse model. (B) Shown are results of quantitative real-time analyses (mRNA copy number per 106 copies of 18S) of PlGF in organs from male FVB mice at various time points after i.p. injection with 18 mg/kg LPS. (C) In situ hybridization (ISH) and immunohistochemistry (IHC) for PlGF in the heart, lung, and liver of male FVB mice treated in the absence (nontreated) or presence of 18 mg/kg LPS at 12 h. The insets in d, h, and i show a higher magnification of a representative area from each field. Arrows indicate PlGF signal. Bar: 50 μm; (insets) 25 μm. (D, a) Survival curves for male PLGF+/+ (wild-type, WT) or PLGF−/− (knockout, KO) mice injected i.p. with 18 mg/kg LPS. (b) Survival curves for female PLGF+/+ (WT) or PLGF−/− (KO) mice injected i.p. with 18 mg/kg LPS. (c) Survival curves for wild-type male mice pretreated with anti-PlGF antibody (PlGF ab) or IgG (CTL ab) and injected i.p. with 18 mg/kg LPS. (d) Survival curves for male PLGF+/+ (WT) or PLGF−/− (KO) mice subjected to CLP. (e) Survival curves for female PLGF+/+ (WT) or PLGF−/− (KO) mice subjected to CLP. (f) Survival curves for wild-type male mice pretreated with anti-PlGF antibody (PlGF ab) or IgG (CTL ab) and subjected to CLP. Data in A and B are expressed as means + SD of at least three independent experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.0001 compared with no treatment (0 h time point).
Mentions: We recently demonstrated that circulating PlGF levels are increased in C57BL/6 mice injected with LPS or subjected to cecal ligation puncture (CLP) (7). The PlGF−/− mice used in this study were backcrossed to an FVB background. Previous studies have demonstrated strain-specific sensitivity to LPS (32–34). Thus, we wished to confirm these findings in FVB mice. The i.p. administration of 18 mg/kg LPS resulted in a time-dependent increase in plasma PlGF concentrations, with peak levels (3,447.4 pg/ml) occurring at 24 h (Fig. 1 A). Similarly, in a CLP model of sepsis, peak levels of PlGF (111.4 pg/ml) occurred at 24 h (Fig. 1 A). Previously, we demonstrated that PlGF protein levels were increased in all tissues examined, including the brain, lung, heart, liver, kidney, and spleen (7). In real-time PCR assays, there was a time-dependent induction of PlGF transcripts at 24 h in the brain (5.3-fold), lung (14.3-fold), liver (28-fold), kidney (25.7-fold), and spleen (8.5-fold). PlGF mRNA levels in the heart peaked at 6 h (54.2-fold; Fig. 1 B). In situ hybridization and immunohistochemical studies revealed a PlGF signal in perivascular cells but not the endothelium (Fig. 1 C shows the heart, lung, and liver). Collectively, these findings suggest that sepsis is associated with the widespread induction of PlGF mRNA and protein expression.

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