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Absence of placental growth factor blocks dextran sodium sulfate-induced colonic mucosal angiogenesis, increases mucosal hypoxia and aggravates acute colonic injury

(2010) LABORATORY INVESTIGATION. 90(4). p.566-576
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Abstract
Angiogenesis has recently been described as a component of inflammatory bowel disease. Placental growth factor (PlGF), a vascular endothelial growth factor (VEGF) homologue, establishes its angiogenic capacity under pathophysiological conditions. We investigated the function of PlGF in experimental models of acute colitis. Acute colonic damage was induced in PlGF knock-out (-/-) mice and PlGF wild-type (+/+) mice by dextran sodium sulfate (DSS) and trinitrobenzenesulfonic acid (TNBS). The concentrations of PlGF and VEGF were measured in distal colonic lysates using an enzyme-linked immunosorbent assay. Colonic injury was evaluated by assessing colon length, colonocyte apoptosis (by terminal dUTP nick-end labeling), colonic cytokine production and histological score. Infiltration of polymorphonuclear cells was determined by assaying myeloperoxidase (MPO) activity. In a separate experiment, recombinant PlGF was administered to PlGF -/- mice by adenoviral transfer before DSS administration. Mucosal vascularization was quantified by computerized morphometric analysis of CD31-stained distal colonic sections. Colonic mucosal hypoxia was visualized by pimonidazole staining. Both VEGF and PlGF were upregulated during acute colitis. In addition, compared with PlGF +/+ controls, PlGF -/- mice showed a significant increase in weight loss and colonic shortening during both DSS and TNBS colitis. This correlated with enhanced colonocyte apoptosis, elevated colonic cytokine levels and increased histological damage score, but not with enhanced inflammatory cell infiltration (MPO activity). The increased morbidity of PlGF -/- mice during DSS colitis was preventable by adenovirus (Ad)-mediated overexpression of PlGF. After the administration of DSS, strongly reduced mucosal angiogenesis was observed in PlGF -/- mice compared with PlGF +/+ mice. This was associated with an early increase in intestinal epithelial pimonidazole accumulation in PlGF -/- mice, suggesting a function of enhanced epithelial hypoxia in the observed differences between the two groups. In summary, our data show that the absence of PlGF strongly inhibits mucosal intestinal angiogenesis in acute colitis, which is associated with an early increase in intestinal epithelial hypoxia and aggravation of the course of the disease.
Keywords
experimental colitis, angiogenesis, inflammatory bowel disease, intestinal mucosal hypoxia, placental growth factor, vascular endothelial growth factor, INFLAMMATORY-BOWEL-DISEASE, EXPERIMENTAL COLITIS, INTESTINAL INFLAMMATION, ULCERATIVE-COLITIS, CROHNS-DISEASE, INHIBITION, APOPTOSIS, PLGF, SEVERITY, THERAPY

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Chicago
HINDRYCKX, PIETER, Anouk Waeytens, Debby Laukens, Harald Peeters, Jacques Vanhuysse, Liesbeth Ferdinande, Peter Carmeliet, and Martine De Vos. 2010. “Absence of Placental Growth Factor Blocks Dextran Sodium Sulfate-induced Colonic Mucosal Angiogenesis, Increases Mucosal Hypoxia and Aggravates Acute Colonic Injury.” Laboratory Investigation 90 (4): 566–576.
APA
HINDRYCKX, P., Waeytens, A., Laukens, D., Peeters, H., Vanhuysse, J., Ferdinande, L., Carmeliet, P., et al. (2010). Absence of placental growth factor blocks dextran sodium sulfate-induced colonic mucosal angiogenesis, increases mucosal hypoxia and aggravates acute colonic injury. LABORATORY INVESTIGATION, 90(4), 566–576.
Vancouver
1.
HINDRYCKX P, Waeytens A, Laukens D, Peeters H, Vanhuysse J, Ferdinande L, et al. Absence of placental growth factor blocks dextran sodium sulfate-induced colonic mucosal angiogenesis, increases mucosal hypoxia and aggravates acute colonic injury. LABORATORY INVESTIGATION. 2010;90(4):566–76.
MLA
HINDRYCKX, PIETER, Anouk Waeytens, Debby Laukens, et al. “Absence of Placental Growth Factor Blocks Dextran Sodium Sulfate-induced Colonic Mucosal Angiogenesis, Increases Mucosal Hypoxia and Aggravates Acute Colonic Injury.” LABORATORY INVESTIGATION 90.4 (2010): 566–576. Print.
@article{845784,
  abstract     = {Angiogenesis has recently been described as a component of inflammatory bowel disease. Placental growth factor (PlGF),
a vascular endothelial growth factor (VEGF) homologue, establishes its angiogenic capacity under pathophysiological
conditions. We investigated the function of PlGF in experimental models of acute colitis. Acute colonic damage was induced in PlGF knock-out (-/-) mice and PlGF wild-type (+/+) mice by dextran sodium sulfate (DSS) and trinitrobenzenesulfonic acid (TNBS). The concentrations of PlGF and VEGF were measured in distal colonic lysates using
an enzyme-linked immunosorbent assay. Colonic injury was evaluated by assessing colon length, colonocyte apoptosis
(by terminal dUTP nick-end labeling), colonic cytokine production and histological score. Infiltration of polymorphonuclear cells was determined by assaying myeloperoxidase (MPO) activity. In a separate experiment, recombinant PlGF was administered to PlGF -/- mice by adenoviral transfer before DSS administration. Mucosal vascularization was quantified by computerized morphometric analysis of CD31-stained distal colonic sections. Colonic mucosal hypoxia was visualized by pimonidazole staining. Both VEGF and PlGF were upregulated during acute colitis. In addition, compared with PlGF +/+ controls, PlGF -/- mice showed a significant increase in weight loss and colonic shortening during both DSS and TNBS colitis. This correlated with enhanced colonocyte apoptosis, elevated colonic cytokine levels and increased
histological damage score, but not with enhanced inflammatory cell infiltration (MPO activity). The increased morbidity of PlGF -/- mice during DSS colitis was preventable by adenovirus (Ad)-mediated overexpression of PlGF. After the administration of DSS, strongly reduced mucosal angiogenesis was observed in PlGF -/- mice compared with PlGF +/+ mice. This was associated with an early increase in intestinal epithelial pimonidazole accumulation in PlGF -/- mice, suggesting a function of enhanced epithelial hypoxia in the observed differences between the two groups. In summary, our data show that the absence of PlGF strongly inhibits mucosal intestinal angiogenesis in acute colitis, which is associated with an early increase in intestinal epithelial hypoxia and aggravation of the course of the disease.},
  author       = {Hindryckx, Pieter and Waeytens, Anouk and Laukens, Debby and Peeters, Harald and Vanhuysse, Jacques and Ferdinande, Liesbeth and Carmeliet, Peter and De Vos, Martine},
  issn         = {0023-6837},
  journal      = {LABORATORY INVESTIGATION},
  language     = {eng},
  number       = {4},
  pages        = {566--576},
  title        = {Absence of placental growth factor blocks dextran sodium sulfate-induced colonic mucosal angiogenesis, increases mucosal hypoxia and aggravates acute colonic injury},
  url          = {http://dx.doi.org/10.1038/labinvest.2010.37},
  volume       = {90},
  year         = {2010},
}

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