Fatty acid binding protein 4 regulates VEGF-induced airway angiogenesis and inflammation in a transgenic mouse model: implications for asthma

Am J Pathol. 2013 Apr;182(4):1425-33. doi: 10.1016/j.ajpath.2012.12.009. Epub 2013 Feb 4.


Neovascularization of the airways occurs in several inflammatory lung diseases, including asthma. Vascular endothelial growth factor (VEGF) plays an important role in vascular remodeling in the asthmatic airways. Fatty acid binding protein 4 (FABP4 or aP2) is an intracellular lipid chaperone that is induced by VEGF in endothelial cells. FABP4 exhibits a proangiogenic function in vitro, but whether it plays a role in modulation of angiogenesis in vivo is not known. We hypothesized that FABP4 promotes VEGF-induced airway angiogenesis and investigated this hypothesis with the use of a transgenic mouse model with inducible overexpression of VEGF165 under a CC10 promoter [VEGF-TG (transgenic) mice]. We found a significant increase in FABP4 mRNA levels and density of FABP4-expressing vascular endothelial cells in mouse airways with VEGF overexpression. FABP4(-/-) mouse airways showed a significant decrease in neovessel formation and endothelial cell proliferation in response to VEGF overexpression. These alterations in airway vasculature were accompanied by attenuated expression of proinflammatory mediators. Furthermore, VEGF-TG/FABP4(-/-) mice showed markedly decreased expression of endothelial nitric oxide synthase, a well-known mediator of VEGF-induced responses, compared with VEGF-TG mice. Finally, the density of FABP4-immunoreactive vessels in endobronchial biopsy specimens was significantly higher in patients with asthma than in control subjects. Taken together, these data unravel FABP4 as a potential target of pathologic airway remodeling in asthma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Asthma / genetics
  • Asthma / metabolism
  • Asthma / pathology*
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Fatty Acid-Binding Proteins / deficiency
  • Fatty Acid-Binding Proteins / metabolism*
  • Female
  • Humans
  • Inflammation / pathology*
  • Lung / blood supply*
  • Lung / drug effects
  • Lung / enzymology
  • Lung / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Neovascularization, Pathologic / metabolism*
  • Neovascularization, Pathologic / pathology
  • Nitric Oxide Synthase Type III / genetics
  • Nitric Oxide Synthase Type III / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / pathology
  • Stem Cell Factor / genetics
  • Stem Cell Factor / metabolism
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor A / pharmacology


  • FABP4 protein, human
  • Fabp4 protein, mouse
  • Fatty Acid-Binding Proteins
  • RNA, Messenger
  • Stem Cell Factor
  • Vascular Endothelial Growth Factor A
  • Nitric Oxide Synthase Type III