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

Objectives: Overexpression of angiopoietin I in the lung has been associated with human pulmonary hypertension. We hypothesized that inhibiting angiopoietin I 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 10(10) 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 I 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 I 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 1and 2 animals treated with AAV-sTIE2. Conclusions: Molecular blocking of the interaction between angiopoietin 1and 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.