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Published ahead of print on April 24, 2003, doi:10.1165/rcmb.2002-0120OC

Am. J. Respir. Cell Mol. Biol., Volume 29, Number 4, October 2003, 449-457

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Submitted on July 17, 2002
Revised on April 18, 2003

Lung overexpression of angiostatin aggravates pulmonary hypertension in chronically hypoxic mice

Marie-Aude PASCAUD1, Franck GRISCELLI2, William RAOUL1, E. MARCOS1, Paule OPOLON2, Bernadette RAFFESTIN3, Francois PERRICAUDET2, Serge ADNOT1*, and Saadia EDDAHIBI1

1 Faculte de medecine, INSERM U492 et AP-HP, Creteil, France, 2 Institut Gustave Roussy, CNRS URA 1301, Villejuif, France, 3 Dpt Physiologie - UFR Paris Ouest, AP-HP - Hop. Ambroise Pare, Boulogne, France

* To whom correspondence should be addressed. E-mail: serge.adnot{at}creteil.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 question 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 molecule 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 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 bronchoalveolarfluid. Mice pretreated with Ad.K3 one day before a two week exposure to hypoxia (10% O2), showed more severe pulmonary hypertension than Ad.CO1-pretreated controls, as assessed by higher right ventricular (RV) systolic pressure (36.5±2.4 vs 30.2±1.4 respectively), aggravation of RV hypertrophy (P<0.05) and muscularization of distal vessels (P<0.01). Lung factor VIII, CD31 immunostaining, as well as eNOS expression 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.




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