Gene transfer of a TIE2 receptor antagonist prevents pulmonary hypertension in rodents.
OBJECTIVE
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 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 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.
Kido
Masakuni
M
Division of Cardiothoracic Surgery, University of California, San Diego 92103-8892, USA.
Du
Lingling
L
Sullivan
Christopher C
CC
Deutsch
Reena
R
Jamieson
Stuart W
SW
Thistlethwaite
Patricia A
PA
D042683:Angiopoietin-1 / Q000235:genetics; D000818:Animals; D001160:Arterioles / Q000473:pathology / Q000503:physiopathology; D000229:Dependovirus / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000187:drug effects / Q000235:genetics; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D008168:Lung / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D008955:Models, Cardiovascular; D011669:Pulmonary Wedge Pressure / Q000187:drug effects / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors*; D012377:Rodentia
D042683:Angiopoietin-1; D042787:Receptor, TIE-2