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Lung Overexpression of Angiostatin Aggravates Pulmonary Hypertension in Chronically Hypoxic Mice

INSERM U 492, Département de Physiologie, CHU Henri Mondor AP-HP, Créteil; CNRS Unité de Recherche Associée 1301/Rhône-Poulenc Rorer Gencell, Institut Gustave Roussy Villejuif; and Département de Physiologie, UFR Paris-Ouest, Hôpital Ambroise Paré AP-HP, Boulogne, France

Address correspondence to: Serge Adnot, INSERM U492, Faculté de Médecine, 8 Rue du Général Sarrail, 94010 Creteil, France. E-mail: eddahibi{at}im3.inserm.fr

Exposure to hypoxia leads to the development of pulmonary hypertension (PH) as a consequence of pulmonary smooth muscle hyperplasia. Hypoxia concomitantly stimulates lung expression of angiogenic factors. To investigate the role of angiogenesis processes in development of hypoxic PH, we examined the effects of lung overexpression of angiostatin, an angiogenesis inhibitor, on development of hypoxic PH and lung endothelial cell (EC) density. Angiostatin delivery was achieved by a defective adenovirus expressing a secretable angiostatin K3 molcule driven by the cytomegalovirus promoter (Ad.K3). Comparison was made with a control vector containing no gene in the expression cassette (Ad.CO1). Treatment with Ad.K3 (300 plaque-forming units [pfu]/cell) inhibited cultured human pulmonary artery EC migration by 100% and proliferation by 50%, but was without effects on human pulmonary artery smooth muscle cells. After intratracheal administration of Ad.K3 (10⁹ pfu) to mice, angiostatin protein became detectable in bronchoalveolar lavage fluid. Mice pretreated with Ad.K3 1 d before a 2-wk exposure to hypoxia (10% O₂) showed more severe pulmonary hypertension than Ad.CO1-pretreated controls, as assessed by higher right ventricular systolic pressure (36.5 ± 2.4 versus 30.2 ± 1.4, respectively), aggravation of right ventricular hypertrophy (P < 0.05), and muscularization of distal vessels (P < 0.01). Lung factor VIII, CD31 immunostaining, as well as eNOS expression were significantly increased after exposure to hypoxia in Ad.CO1-pretreated controls, but decreased in both normoxic and hypoxic animals after treatment with Ad.K3. The results show that inhibition of hypoxia-induced stimulation of lung angiogenic processes aggravates development of hypoxic PH. This suggests that endogenous lung angiogenesis counteracts development of hypoxic PH.

Abbreviations: Dulbecco's modified Eagle's medium, DMEM • endothelial cell, EC • fetal calf serum, FCS • fibroblast growth factor, FGF • human microvascular endothelial cells, HMEC • microculture tetrazolium, MTT • pulmonary arterial smooth muscle cells, PA-SMC • platelet-derived growth factor, PDGF • plaque-forming units, pfu • pulmonary hypertension, PH • vascular endothelial growth factor, VEGF

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