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Am. J. Respir. Cell Mol. Biol., Volume 23, Number 6, December, 2000 762-771

Adenovirus-Mediated Lung Vascular Endothelial Growth Factor Overexpression Protects against Hypoxic Pulmonary Hypertension in Rats

Chohreh Partovian, Serge Adnot, Bernadette Raffestin, Vanessa Louzier, Micheline Levame, Isabelle Macquin Mavier, Patricia Lemarchand, and Saadia Eddahibi

INSERM U492, Département de Physiologie et Service de Pharmacologie Clinique, Hôpital Henri Mondor, Créteil; Département de Physiologie, Hôpital Ambroise Paré, Boulogne; and INSERM U25, Hôpital Necker-Enfants-Malades, Paris, France

Chronic hypoxic pulmonary hypertension (PH) is associated with vasoconstriction 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 factor (VEGF) is beneficial in hypoxic PH, recombinant adenovirus encoding the human VEGF 165 gene under the control of a cytomegalovirus promoter (Ad.VEGF) or control vector containing no gene in the expression cassette (Ad.Null) was administered intratracheally to rats. With Ad.VEGF (108 plaque-forming units [pfu]), VEGF protein was present in bronchoalveolar lavage fluid 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 change in lung permeability. In rats pretreated with Ad.VEGF (108 pfu) 2 d before a 2-wk exposure to hypoxia (10% O2), lower values versus Ad.Null-pretreated controls were found for pulmonary artery pressure (25 ± 1 versus 30 ± 2 mm Hg, P < 0.05), right ventricular over left ventricular-plus-septum weight (0.37 ± 0.01 versus 0.47 ± 0.02, P < 0.001), normalized wall thickness of 50- to 200-µm vessels (P < 0.001), and muscularization of distal vessels (P < 0.001). Pretreatment with Ad.VEGF (108 pfu) increased endothelial nitric oxide synthase activity in lung tissue and partially restored endothelium-dependent vasodilation in isolated lungs from chronically hypoxic rats, as assessed by improvement of ionophore A23187-induced vasodilation and attenuation of endothelin-1 (300 pmol)-induced vasoconstriction, an effect abolished in the presence of nitro-L-arginine methylester. We conclude that adenoviral-mediated VEGF overexpression in the lungs attenuates development of hypoxic PH, in part by protecting endothelium-dependent function.




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