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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 mRNA/protein levels of inflammatory and hemostatic markers in a mouse model of endotoxemia. PLGF+/+ (WT) or PLGF−/− (KO) male mice were injected i.p. with or without 16 mg/kg LPS. (A) Shown are the results of quantitative real-time PCR analyses (mRNA copy number per 106 copies of 18S) of ICAM-1, VCAM-1, E-selectin, P-selectin, COX-2, and PAI-1 in the heart, lung and liver at 24 h. Data are expressed as means + SD of three independent experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.0001 compared with untreated controls (and where indicated between PlGF-deficient and wild-type mice). (B) Double immunofluorescence staining for activation markers and CD31 in the liver of wild-type mice treated in the absence (WT) or presence of 16 mg/kg LPS (WT/L) and PlGF−/− mice treated with 16 mg/kg LPS (PKO/L) at 24 h. (a) ICAM-1 (green) and CD31 (red). (b) VCAM-1 (green) and CD31 (red). (c) E-selectin (green) and CD31 (red). (d) P-selectin (green) and CD31 (red). (e) COX-2 (red) and CD31 (green). (f) PAI-1 (red) and CD31 (green). Bars: 132 μm; (insets) 42 μm.
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fig4: Effect of PlGF deficiency on tissue mRNA/protein levels of inflammatory and hemostatic markers in a mouse model of endotoxemia. PLGF+/+ (WT) or PLGF−/− (KO) male mice were injected i.p. with or without 16 mg/kg LPS. (A) Shown are the results of quantitative real-time PCR analyses (mRNA copy number per 106 copies of 18S) of ICAM-1, VCAM-1, E-selectin, P-selectin, COX-2, and PAI-1 in the heart, lung and liver at 24 h. Data are expressed as means + SD of three independent experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.0001 compared with untreated controls (and where indicated between PlGF-deficient and wild-type mice). (B) Double immunofluorescence staining for activation markers and CD31 in the liver of wild-type mice treated in the absence (WT) or presence of 16 mg/kg LPS (WT/L) and PlGF−/− mice treated with 16 mg/kg LPS (PKO/L) at 24 h. (a) ICAM-1 (green) and CD31 (red). (b) VCAM-1 (green) and CD31 (red). (c) E-selectin (green) and CD31 (red). (d) P-selectin (green) and CD31 (red). (e) COX-2 (red) and CD31 (green). (f) PAI-1 (red) and CD31 (green). Bars: 132 μm; (insets) 42 μm.

Mentions: Compared with wild-type controls, endotoxemic PlGF−/− mice demonstrated significant vascular bed–specific changes in the expression of inflammatory and procoagulant molecules (Fig. 4; and Fig. S1, available at http://www.jem.org/cgi/content/full/jem.20080398/DC1). Specifically, PlGF deficiency resulted in increased expression of intercellular adhesion molecule (ICAM)–1 in the heart (1.9-fold), lung (1.7-fold), liver (6.5-fold), kidney (2.7-fold), and spleen (1.4-fold); increased expression of vascular cell adhesion molecule (VCAM)–1 in the liver (2.9-fold); increased E-selectin expression in the heart (2.8-fold) and liver (6.9-fold) but decreased E-selectin expression in the lung (0.5-fold); increased P-selectin expression in the lung (1.5-fold) and liver (3.7-fold); increased cyclooxygenase (COX)-2 expression in the heart (2.9-fold), liver (47.5-fold), kidney (5.7-fold), and spleen (4.5-fold); and increased plasminogen activator inhibitor (PAI)–1 in the liver (5.3-fold) and decreased PAI-1 in the heart (0.3-fold), brain (0.3-fold), kidney (0.6-fold), and spleen (0.3-fold; Fig. 4 A and Fig. S1).


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 mRNA/protein levels of inflammatory and hemostatic markers in a mouse model of endotoxemia. PLGF+/+ (WT) or PLGF−/− (KO) male mice were injected i.p. with or without 16 mg/kg LPS. (A) Shown are the results of quantitative real-time PCR analyses (mRNA copy number per 106 copies of 18S) of ICAM-1, VCAM-1, E-selectin, P-selectin, COX-2, and PAI-1 in the heart, lung and liver at 24 h. Data are expressed as means + SD of three independent experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.0001 compared with untreated controls (and where indicated between PlGF-deficient and wild-type mice). (B) Double immunofluorescence staining for activation markers and CD31 in the liver of wild-type mice treated in the absence (WT) or presence of 16 mg/kg LPS (WT/L) and PlGF−/− mice treated with 16 mg/kg LPS (PKO/L) at 24 h. (a) ICAM-1 (green) and CD31 (red). (b) VCAM-1 (green) and CD31 (red). (c) E-selectin (green) and CD31 (red). (d) P-selectin (green) and CD31 (red). (e) COX-2 (red) and CD31 (green). (f) PAI-1 (red) and CD31 (green). Bars: 132 μm; (insets) 42 μm.
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fig4: Effect of PlGF deficiency on tissue mRNA/protein levels of inflammatory and hemostatic markers in a mouse model of endotoxemia. PLGF+/+ (WT) or PLGF−/− (KO) male mice were injected i.p. with or without 16 mg/kg LPS. (A) Shown are the results of quantitative real-time PCR analyses (mRNA copy number per 106 copies of 18S) of ICAM-1, VCAM-1, E-selectin, P-selectin, COX-2, and PAI-1 in the heart, lung and liver at 24 h. Data are expressed as means + SD of three independent experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.0001 compared with untreated controls (and where indicated between PlGF-deficient and wild-type mice). (B) Double immunofluorescence staining for activation markers and CD31 in the liver of wild-type mice treated in the absence (WT) or presence of 16 mg/kg LPS (WT/L) and PlGF−/− mice treated with 16 mg/kg LPS (PKO/L) at 24 h. (a) ICAM-1 (green) and CD31 (red). (b) VCAM-1 (green) and CD31 (red). (c) E-selectin (green) and CD31 (red). (d) P-selectin (green) and CD31 (red). (e) COX-2 (red) and CD31 (green). (f) PAI-1 (red) and CD31 (green). Bars: 132 μm; (insets) 42 μm.
Mentions: Compared with wild-type controls, endotoxemic PlGF−/− mice demonstrated significant vascular bed–specific changes in the expression of inflammatory and procoagulant molecules (Fig. 4; and Fig. S1, available at http://www.jem.org/cgi/content/full/jem.20080398/DC1). Specifically, PlGF deficiency resulted in increased expression of intercellular adhesion molecule (ICAM)–1 in the heart (1.9-fold), lung (1.7-fold), liver (6.5-fold), kidney (2.7-fold), and spleen (1.4-fold); increased expression of vascular cell adhesion molecule (VCAM)–1 in the liver (2.9-fold); increased E-selectin expression in the heart (2.8-fold) and liver (6.9-fold) but decreased E-selectin expression in the lung (0.5-fold); increased P-selectin expression in the lung (1.5-fold) and liver (3.7-fold); increased cyclooxygenase (COX)-2 expression in the heart (2.9-fold), liver (47.5-fold), kidney (5.7-fold), and spleen (4.5-fold); and increased plasminogen activator inhibitor (PAI)–1 in the liver (5.3-fold) and decreased PAI-1 in the heart (0.3-fold), brain (0.3-fold), kidney (0.6-fold), and spleen (0.3-fold; Fig. 4 A and Fig. S1).

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