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J Thorac Cardiovasc Surg 2005;129:268-276
© 2005 The American Association for Thoracic Surgery

General Thoracic Surgery

Gene transfer of a TIE2 receptor antagonist prevents pulmonary hypertension in rodents

^a Division of Cardiothoracic Surgery
^b Division of Biostatistics, University of California, San Diego, San Diego, Calif

Read at the Eighty-fourth Annual Meeting of The American Association for Thoracic Surgery, Toronto, Ontario, Canada, April 25-28, 2004.

Received for publication March 30, 2004; revisions received September 1, 2004; accepted for publication September 27, 2004.

^* Address for reprints: Patricia A. Thistlethwaite, MD, PhD, Division of Cardiothoracic Surgery, University of California, San Diego, San Diego, CA 92103-8892 (E-mail: pthistlethwaite{at}ucsd.edu).

OBJECTIVES: Overexpression of angiopoietin 1 in the lung has been associated with human pulmonary hypertension. We hypothesized that inhibiting angiopoietin 1 signaling in the lung by administration of a receptor antagonist would block the development of pulmonary hypertensive vasculopathy in rodent models.

METHODS: We injected 2 and 4 x 10¹⁰ genomic particles of adeno-associated virus containing an extracellular fragment of the TIE2 receptor (AAV-sTIE2) into the pulmonary artery of 60 rats by using adeno-associated virus–lacZ and carrier-injected rats as control animals. Pulmonary hypertension was then induced by each of the following methods: (1) monocrotaline (group 1); (2) angiopoietin 1 expression in pulmonary vascular smooth muscle by adeno-associated virus gene transfer (group 2); or (3) oxygen deprivation (group 3). Animals were sacrificed at serial time points. At each time point, pulmonary artery pressures were measured, and pulmonary angiography was performed. Lungs were harvested for pathologic-molecular analysis.

RESULTS: Each rodent pulmonary hypertension model demonstrated a significant increase in pulmonary artery pressures compared with that seen in control animals (P < .01). Administration of AAV-sTIE2 prevented pulmonary hypertension in the monocrotaline and angiopoietin 1 groups (from 44.6 ± 2.1 to 18.8 ± 1.9 mm Hg in the monocrotaline group and from 31.2 ± 3.7 to 18.2 ± 1.8 mm Hg in the angiopoietin 1 group, P < .001) but did not affect pulmonary hypertension in the hypoxia group. Pathologic analysis of group 1 and 2 lungs treated with AAV-sTIE2 demonstrated absence of smooth muscle cell proliferation within arterioles. Pulmonary angiography confirmed a lack of small pulmonary vessel occlusion in group 1 and 2 animals treated with AAV-sTIE2.

CONCLUSIONS: Molecular blocking of the interaction between angiopoietin 1 and its endothelial receptor, TIE2, in the lung prevents pulmonary hypertension in 2 animal models of the disease. These experiments suggest a new strategy for understanding pulmonary hypertension based on the molecular biology of the pulmonary vascular wall.

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