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Ann Thorac Surg 2004;77:449-456
© 2004 The Society of Thoracic Surgeons

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Original article: general thoracic

A new animal model for pulmonary hypertension based on the overexpression of a single gene, angiopoietin-1

^a Division of Cardiothoracic Surgery, University of California, San Diego, California, USA
^b Department of Pathology, Veterans Administration Medical Center, La Jolla, California, USA
^c Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California, USA

Accepted for publication April 28, 2003.

^* Address reprint requests to Dr Thistlethwaite, Division of Cardiothoracic Surgery, University of California, San Diego, 200 West Arbor Dr, San Diego, CA 92103-8892, USA
e-mail: pthistlethwaite{at}ucsd.edu

BACKGROUND: Angiopoietin-1 gene expression in human pulmonary hypertensive lungs is directly proportional to increasing pulmonary vascular resistance. We hypothesized that targeted overexpresssion of angiopoietin-1 in the lung would cause persistent pulmonary hypertension in an animal model.

METHODS: We injected 2 x 10¹⁰ genomic particles of adeno-associated virus-angiopoietin-1 (AAV-Ang-1) into the right ventricular outflow tract of 30 Fischer rats while using adeno-associated virus-lacZ (AAV-lacZ) injected rats and carrier-injected rats as our control groups. All animals underwent survival surgery and were sacrificed at serial timepoints postgene delivery. At each timepoint, pulmonary artery pressures were measured and pulmonary angiography using the Microfil polymer perfusion technique was performed. The lungs were harvested for pathologic analysis, mRNA analysis, Western blot assays, and in situ RNA hybridization to localize gene expression.

RESULTS: Pulmonary artery pressures of AAV-Ang-1 injected rats were significantly increased compared with the control groups (p < 0.01) at all timepoints. Pathologic analysis of AAV-Ang-1 lung specimens demonstrated increased smooth muscle cell proliferation within the medial layer of arterioles with obliteration of small vessels similar to that seen in human pulmonary hypertension. Angiograms of AAV-Ang-1 injected lungs showed blunting of small peripheral arterioles consistent with advanced pulmonary hypertension. In situ RNA hybridization localized angiopoietin-1 expression to the vascular wall of small-caliber pulmonary vessels. Protein and mRNA assays confirmed persistent angiopoietin-1 expression in the lung for up to 60 days postgene delivery.

CONCLUSIONS: Overexpression of angiopoietin-1 using an adeno-associated virus vector causes pulmonary hypertension in rats. These data provide a novel physiologic animal model for pulmonary hypertension.

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