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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 cardiac function and vascular permeability in a mouse model of endotoxemia. (A, a and b) PLGF+/+ (WT) or PLGF−/− (KO) male mice were injected i.p. with or without 16 mg/kg LPS and were subjected to echocardiogram and electrocardiogram 24 h later. Shown are quantitative analyses for heart rate (HR) and fractional shortening (FS). (c and d) Same as in a and b 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, a) PLGF+/+ (WT, W) or PLGF−/− (KO, K) male mice were injected i.p. with or without 16 mg/kg LPS. 24 h later, the animals were injected i.v. with 0.1 ml 1% Evans blue dye. After 40 min, the mice were perfused, and the brain, lung, heart, liver, kidney, and spleen were harvested and incubated in formamide for 3 d to elute Evans blue dye. Shown is the quantitation of Evans blue extravasation (OD = 620 nm). (b) Same as in a except that wild-type mice were pretreated with anti-PlGF antibody (PlGF ab, P) or IgG (CTL IgG, C) and injected i.p. with or without 16 mg/kg LPS. Data are expressed as means + SD of three independent experiments. *, P < 0.05; and **, P < 0.01 compared with the respective untreated controls (and where indicated between PlGF-deficient and wild-type mice).
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fig3: Effect of PlGF deficiency on cardiac function and vascular permeability in a mouse model of endotoxemia. (A, a and b) PLGF+/+ (WT) or PLGF−/− (KO) male mice were injected i.p. with or without 16 mg/kg LPS and were subjected to echocardiogram and electrocardiogram 24 h later. Shown are quantitative analyses for heart rate (HR) and fractional shortening (FS). (c and d) Same as in a and b 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, a) PLGF+/+ (WT, W) or PLGF−/− (KO, K) male mice were injected i.p. with or without 16 mg/kg LPS. 24 h later, the animals were injected i.v. with 0.1 ml 1% Evans blue dye. After 40 min, the mice were perfused, and the brain, lung, heart, liver, kidney, and spleen were harvested and incubated in formamide for 3 d to elute Evans blue dye. Shown is the quantitation of Evans blue extravasation (OD = 620 nm). (b) Same as in a except that wild-type mice were pretreated with anti-PlGF antibody (PlGF ab, P) or IgG (CTL IgG, C) and injected i.p. with or without 16 mg/kg LPS. Data are expressed as means + SD of three independent experiments. *, P < 0.05; and **, P < 0.01 compared with the respective untreated controls (and where indicated between PlGF-deficient and wild-type mice).

Mentions: Consistent with our previous results (7), systemic administration of LPS or CLP in mice resulted in marked depression of cardiac function, as indicated by reduced fractional shortening and heart rate on echocardiography (Fig. 3 A). The effect of endotoxin on fractional shortening was accentuated in PlGF−/− mice (Fig. 3 A, b) and in wild-type mice administered PlGF antibody (Fig. 3 A, d). Endotoxemic-associated bradycardia was accentuated by PlGF antibody (Fig. 3 A, c). PlGF deficiency was also associated with an accentuation of barrier dysfunction. Compared with wild-type mice, LPS administration in PlGF−/− mice resulted in increased extravasation of Evans blue dye in the liver and spleen (Fig. 3 B, a). Antibody-mediated depletion of PlGF resulted in increased extravasation occurring in the lung, liver, and kidney (Fig. 3 B, b). Collectively, these findings suggest that PlGF deficiency is associated with impaired cardiac function and organ-specific accentuation of vascular permeability during 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 cardiac function and vascular permeability in a mouse model of endotoxemia. (A, a and b) PLGF+/+ (WT) or PLGF−/− (KO) male mice were injected i.p. with or without 16 mg/kg LPS and were subjected to echocardiogram and electrocardiogram 24 h later. Shown are quantitative analyses for heart rate (HR) and fractional shortening (FS). (c and d) Same as in a and b 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, a) PLGF+/+ (WT, W) or PLGF−/− (KO, K) male mice were injected i.p. with or without 16 mg/kg LPS. 24 h later, the animals were injected i.v. with 0.1 ml 1% Evans blue dye. After 40 min, the mice were perfused, and the brain, lung, heart, liver, kidney, and spleen were harvested and incubated in formamide for 3 d to elute Evans blue dye. Shown is the quantitation of Evans blue extravasation (OD = 620 nm). (b) Same as in a except that wild-type mice were pretreated with anti-PlGF antibody (PlGF ab, P) or IgG (CTL IgG, C) and injected i.p. with or without 16 mg/kg LPS. Data are expressed as means + SD of three independent experiments. *, P < 0.05; and **, P < 0.01 compared with the respective untreated controls (and where indicated between PlGF-deficient and wild-type mice).
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fig3: Effect of PlGF deficiency on cardiac function and vascular permeability in a mouse model of endotoxemia. (A, a and b) PLGF+/+ (WT) or PLGF−/− (KO) male mice were injected i.p. with or without 16 mg/kg LPS and were subjected to echocardiogram and electrocardiogram 24 h later. Shown are quantitative analyses for heart rate (HR) and fractional shortening (FS). (c and d) Same as in a and b 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, a) PLGF+/+ (WT, W) or PLGF−/− (KO, K) male mice were injected i.p. with or without 16 mg/kg LPS. 24 h later, the animals were injected i.v. with 0.1 ml 1% Evans blue dye. After 40 min, the mice were perfused, and the brain, lung, heart, liver, kidney, and spleen were harvested and incubated in formamide for 3 d to elute Evans blue dye. Shown is the quantitation of Evans blue extravasation (OD = 620 nm). (b) Same as in a except that wild-type mice were pretreated with anti-PlGF antibody (PlGF ab, P) or IgG (CTL IgG, C) and injected i.p. with or without 16 mg/kg LPS. Data are expressed as means + SD of three independent experiments. *, P < 0.05; and **, P < 0.01 compared with the respective untreated controls (and where indicated between PlGF-deficient and wild-type mice).
Mentions: Consistent with our previous results (7), systemic administration of LPS or CLP in mice resulted in marked depression of cardiac function, as indicated by reduced fractional shortening and heart rate on echocardiography (Fig. 3 A). The effect of endotoxin on fractional shortening was accentuated in PlGF−/− mice (Fig. 3 A, b) and in wild-type mice administered PlGF antibody (Fig. 3 A, d). Endotoxemic-associated bradycardia was accentuated by PlGF antibody (Fig. 3 A, c). PlGF deficiency was also associated with an accentuation of barrier dysfunction. Compared with wild-type mice, LPS administration in PlGF−/− mice resulted in increased extravasation of Evans blue dye in the liver and spleen (Fig. 3 B, a). Antibody-mediated depletion of PlGF resulted in increased extravasation occurring in the lung, liver, and kidney (Fig. 3 B, b). Collectively, these findings suggest that PlGF deficiency is associated with impaired cardiac function and organ-specific accentuation of vascular permeability during 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