title: VEGFR-2 reduces while combined VEGFR-2 and -3 signaling increases inflammation in apical periodontitis.
abstract: BACKGROUND
  In apical periodontitis, oral pathogens provoke an inflammatory response in the apical area that induces bone resorptive lesions. In inflammation, angio- and lymphangiogenesis take place. Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are key players in these processes and are expressed in immune cells and endothelial cells in the lesions.
  
  
  OBJECTIVE
  We aimed at testing the role of VEGFR-2 and -3 in periapical lesion development and investigated their role in lymphangiogenesis in the draining lymph nodes.
  
  
  METHODS
  We induced lesions by pulp exposure in the lower first molars of C57BL/6 mice. The mice received IgG injections or blocking antibodies against VEGFR-2 (anti-R2), VEGFR-3 (anti-R3), or combined VEGFR-2 and -3, starting on day 0 until day 10 or 21 post-exposure.
  
  
  RESULTS
  Lesions developed faster in the anti-R2 and anti-R3 group than in the control and anti-R2/R3 groups. In the anti-R2 group, a strong inflammatory response was found expressed as increased number of neutrophils and osteoclasts. A decreased level of pro-inflammatory cytokines was found in the anti-R2/R3 group. Lymphangiogenesis in the draining lymph nodes was inhibited after blocking of VEGFR-2 and/or -3, while the largest lymph node size was seen after anti-R2 treatment.
  
  
  CONCLUSIONS
  We demonstrate an anti-inflammatory effect of VEGFR-2 signaling in periapical lesions which seems to involve neutrophil regulation and is independent of angiogenesis. Combined signaling of VEGFR-2 and -3 has a pro-inflammatory effect. Lymph node lymphangiogenesis is promoted through activation of VEGFR-2 and/or VEGFR-3.
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway; anca.virtej@uib.no.
authors.forename: Anca
authors.initials: A
authors.lastname: Virtej
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Panagiota
authors.initials: P
authors.lastname: Papadakou
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.
authors.forename: Hajime
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: Department of Clinical Dentistry, University of Bergen, Bergen, Norway.
authors.forename: Athanasia
authors.initials: A
authors.lastname: Bletsa
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Ellen
authors.initials: E
authors.lastname: Berggreen
keywords: angiogenesis and lymphangiogenesis; bone resorption; cytokines; immune cells; osteoclasts