Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality
| Autor: | Peter Carmeliet, William C. Aird, Natalya Bodyak, Kiichiro Yano, Peter M. Kang, S. Ananth Karumanchi, Joseph P. Mizgerd, Bryan Belikoff, Hitomi Okada, Janet Mullington, Patricia C. Liaw, Benjamin T. Simms, Shu-Ching Shih, Jon A. Buras, Lisa J. Toltl |
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| Rok vydání: | 2006 |
| Předmět: |
Lipopolysaccharides
Vascular Endothelial Growth Factor A Placental growth factor Immunology Inflammation Vascular permeability Pregnancy Proteins 030204 cardiovascular system & hematology Article Sepsis Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Animals Humans Immunology and Allergy Cecum Placenta Growth Factor 030304 developmental biology 0303 health sciences business.industry Articles medicine.disease Endotoxemia Pathophysiology 3. Good health Vascular endothelial growth factor Disease Models Animal Vascular endothelial growth factor A chemistry medicine.symptom business Soluble fms-like tyrosine kinase-1 |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| DOI: | 10.1084/jem.20060375 |
| Popis: | Sepsis, the systemic inflammatory response to infection, is a leading cause of morbidity and mortality. The mechanisms of sepsis pathophysiology remain obscure but are likely to involve a complex interplay between mediators of the inflammatory and coagulation pathways. An improved understanding of these mechanisms should provide an important foundation for developing novel therapies. In this study, we show that sepsis is associated with a time-dependent increase in circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in animal and human models of sepsis. Adenovirus-mediated overexpression of soluble Flt-1 (sFlt-1) in a mouse model of endotoxemia attenuated the rise in VEGF and PlGF levels and blocked the effect of endotoxemia on cardiac function, vascular permeability, and mortality. Similarly, in a cecal ligation puncture (CLP) model, adenovirus–sFlt-1 protected against cardiac dysfunction and mortality. When administered in a therapeutic regimen beginning 1 h after the onset of endotoxemia or CLP, sFlt peptide resulted in marked improvement in cardiac physiology and survival. Systemic administration of antibodies against the transmembrane receptor Flk-1 but not Flt-1 protected against sepsis mortality. Adenovirus-mediated overexpression of VEGF but not PlGF exacerbated the lipopolysaccharide-mediated toxic effects. Together, these data support a pathophysiological role for VEGF in mediating the sepsis phenotype. |
| Databáze: | OpenAIRE |
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