title: Mast cells can mediate vascular permeability through regulation of the PI3K-HIF-1alpha-VEGF axis.
abstract: BACKGROUND
  Bronchial inflammation is usually accompanied by increased vascular permeability. Mast cells release a number of mediators that act directly on the vasculature, resulting in vasodilatation, increased permeability, and subsequent plasma protein extravasation. Vascular endothelial growth factor (VEGF) has been implicated to contribute to asthmatic tissue edema through its effect on vascular permeability. However, the effects of mast cells on VEGF-mediated signaling in allergic airway disease are not clearly understood.
  
  
  OBJECTIVE
  An aim of the present study was to investigate the role of mast cells on VEGF-mediated signal transduction in allergic airway disease.
  
  
  METHODS
  We used genetically mast cell-deficient WBB6F(1)-Kit(W)/Kit(W-v) (W/W(v)) mice and the congenic normal WBB6F(1)(+/+) mouse model for allergic airway disease to investigate the role of mast cells on VEGF-mediated signal transduction in allergic airway disease, more specifically in vascular permeability.
  
  
  RESULTS
  Our present study, with ovalbumin (OVA)-sensitized without adjuvant and OVA-challenged mice, revealed the following typical pathophysiologic features of allergic airway diseases: increased inflammatory cells of the airways, airway hyperresponsiveness, increased vascular permeability, and increased levels of VEGF. However, levels of VEGF and plasma exudation in W/W(v) mice after OVA inhalation were significantly lower than levels in WBB6F(1)(+/+) mice. Moreover, mast cell-reconstituted W/W(v) mice restored vascular permeability and VEGF levels similar to those of the WBB6F(1)(+/+) mice. Our data also showed that VEGF expression was regulated by hypoxia-inducible factor-1alpha (HIF-1alpha) activation through the phosphatidylinositol 3-kinase (PI3K)-HIF-1alpha pathway in allergic airway disease.
  
  
  CONCLUSIONS
  These results suggest that mast cells modulate vascular permeability by the regulation of the PI3K-HIF-1alpha-VEGF axis.
authors.affiliation: Department of Internal Medicine, Chonbuk National University Medical School, San 2-20, Geumam-dong, Deokjin-gu, Jeonju, 561-180, South Korea.
authors.forename: Kyung Sun
authors.initials: KS
authors.lastname: Lee
authors.forename: So Ri
authors.initials: SR
authors.lastname: Kim
authors.forename: Seoung Ju
authors.initials: SJ
authors.lastname: Park
authors.forename: Kyung Hoon
authors.initials: KH
authors.lastname: Min
authors.forename: Ka Young
authors.initials: KY
authors.lastname: Lee
authors.forename: Yeong Hun
authors.initials: YH
authors.lastname: Choe
authors.forename: Seung Yong
authors.initials: SY
authors.lastname: Park
authors.forename: Ok Hee
authors.initials: OH
authors.lastname: Chai
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Chang Ho
authors.initials: CH
authors.lastname: Song
authors.forename: Yong Chul
authors.initials: YC
authors.lastname: Lee
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002199:Capillary Permeability / Q000502:physiology*; D003720:Densitometry; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D008407:Mast Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D019869:Phosphatidylinositol 3-Kinases