Lee CG, Link H, Baluk P, et al. Nat Med. 2004;10:1095–1103
Purpose of the Study.
To evaluate the role of vascular endothelial growth factor (VEGF) in T-helper type 2 (Th2) cell-mediated airway inflammation.
Lung-targeted VEGF165 transgenic mice and wild-type mice.
Phenotypes of transgenic mice with elevated VEGF induced by doxycycline were studied and compared with wild-type mice. Airway histologic and physiologic assessments with special stains of microvasculatures, epithelium cells, inflammatory cells, smooth muscle cells, and dendritic cells (DCs) as well as allergen sensitization and methacholine tests were performed.
Both Th2 and epithelial cells were primary sources of VEGF. Mice with overexpressed VEGF in the airways demonstrated increased neovascularization, mucous gland metaplasia, edema, collagen deposition, myocyte hyperplasia with enlarged smooth muscle bundles, inflammatory cells, activated DCs, airway hyperresponsiveness, interleukin 13 mRNA expression, Th2 responses, and allergen sensitization.
VEGF is a potent mediator of allergic airway inflammation by enhancing allergen sensitization, airway hyperresponsiveness, Th2 inflammation, and airway remodeling.
Well-described airway pathology in asthma includes epithelial desquamation, goblet cell hyperplasia, collagen deposition below the basement membrane, smooth muscle hypertrophy/hyperplasia, and the growth and proliferation of new blood vessels. Although its pathogenesis is still unclear, VEGF (an inducer of angiogenesis) recently attracted considerable attention as a major contributor to airway remodeling. VEGF was first discovered as a vascular permeability factor >20 years ago. Subsequently, it was revealed to be a potent inducer of endothelial cell activation and growth. Overexpression of VEGF and its receptor in the airways has been demonstrated in stable asthma and during asthma exacerbations and are reduced by conventional asthma therapies (ie, inhaled corticosteroids and leukotriene receptor antagonists). The findings of this study imply an essential role of VEGF in asthma pathogenesis with links to Th2-mediated airway inflammation and remodeling. The results of this study may also inform the link of respiratory syncytial virus infection and asthma development in children, because respiratory syncytial virus up-regulates VEGF production. This disclosed role of VEGF highlights a potential therapeutic role for a VEGF receptor antagonist in asthma.