Adenovirus-mediated lung vascular endothelial growth factor overexpressionprotects against hypoxic pulmonary hypertension in rats

Chronic hypoxic pulmonary hypertension (PH) is associated with vasoconstric tion and structural remodeling of pulmonary vessels including narrowing of the arterial lumen and loss of distal functional arteries. To test whether lung overexpression of the angiogenic factor vascular endothelial growth fa ctor (VEGF) is beneficial in hypoxic PH, recombinant adenovirus encoding th e human VEGF 165 gene under the control of a cytomegalovirus promoter (Ad.V EGF) or control vector containing no gene in the expression cassette (Ad.Nu ll) was administered intratracheally to rats. With Ad.VEGF (10(8) plaque-fo rming units [pfu]), VEGF protein was present in bronchoalveolar ravage flui d as early as 2 d and until 17 d after gene transfer, but was not detected in serum. Only small patchy areas of mononuclear cells without cell damage, edema, or hemorrhage were observed on lung histology with no significant c hange in lung permeability. In rats pretreated with Ad.VEGF (10(8) pfu) 2 d before a 2-wk exposure to hypoxia (10% O-2), lower values versus Ad.Null-p retreated controls were found for pulmonary artery pressure (25 +/- 1 versu s 30 +/- 2 mm Hg, P < 0.05), right ventricular over left ventricular-plus-s eptum weight (0.37 +/- 0.01 versus 0.47 +/- 0.02, P < 0.001), normalized wa ll thickness of 50- to 200-mum vessels (P < 0.001), and muscularization of distal vessels (P < 0.001). Pretreatment with Ad.VEGF (108 pfu) increased e ndothelial nitric oxide synthase activity in lung tissue and partially rest ored endothelium-dependent vasodilation in isolated lungs from chronically hypoxic rats, as assessed by improvement of ionophore A23187-induced vasodi lation and attenuation of endothelin-1 (300 pmol)-induced vasoconstriction, an effect abolished in the presence of nitro-1-arginine methylester. We co nclude that adenoviral-mediated VEGF overexpression in the lungs attenuates development of hypoxic PH, in part by protecting endothelium-dependent fun ction.