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(Circulation. 2005;111:2988-2996.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Development of Occlusive Neointimal Lesions in Distal Pulmonary Arteries of Endothelin B Receptor–Deficient Rats

A New Model of Severe Pulmonary Arterial Hypertension

D. Dunbar Ivy, MD; Ivan F. McMurtry, PhD; Kelley Colvin, MS; Masatoshi Imamura, MD; Masahiko Oka, MD, PhD; Dong-Seok Lee, MD; Sarah Gebb, PhD; Peter Lloyd Jones, PhD

From the Sections of Pediatric Cardiology (D.D.I., K.C., D.L.), Cardiovascular Pulmonary Research Laboratory (I.F.M., M.I., M.O., S.G.), and Critical Care and Developmental Lung Biology (P.L.J.), University of Colorado School of Medicine and Children’s Hospital, Denver.

Correspondence to D. Dunbar Ivy, MD, Department of Cardiology, Box B100, Children’s Hospital, 1056 E 19th Ave, Denver, CO 80218. E-mail ivy.dunbar{at}tchden.org

Received July 11, 2004; revision received January 27, 2005; accepted February 3, 2005.

Background— Human pulmonary arterial hypertension (PAH) is characterized by proliferation of vascular smooth muscle and, in its more severe form, by the development of occlusive neointimal lesions. However, few animal models of pulmonary neointimal proliferation exist, thereby limiting a complete understanding of the pathobiology of PAH. Recent studies of the endothelin (ET) system demonstrate that deficiency of the ET_B receptor predisposes adult rats to acute and chronic hypoxic PAH, yet these animals fail to develop neointimal lesions. Herein, we determined and thereafter showed that exposure of ET_B receptor–deficient rats to the endothelial toxin monocrotaline (MCT) leads to the development of neointimal lesions that share hallmarks of human PAH.

Methods and Results— The pulmonary hemodynamic and morphometric effects of 60 mg/kg MCT in control (MCT^+/+) and ET_B receptor–deficient (MCT^sl/sl) rats at 6 weeks of age were assessed. MCT^sl/sl rats developed more severe PAH, characterized by elevated pulmonary artery pressure, diminished cardiac output, and right ventricular hypertrophy. In MCT^sl/sl rats, morphometric evaluation revealed the presence of neointimal lesions within small distal pulmonary arteries, increased medial wall thickness, and decreased arterial-to-alveolar ratio. In keeping with this, barium angiography revealed diminished distal pulmonary vasculature of MCT^sl/sl rat lungs. Cells within neointimal lesions expressed smooth muscle and endothelial cell markers. Moreover, cells within neointimal lesions exhibited increased levels of proliferation and were located in a tissue microenvironment enriched with vascular endothelial growth factor, tenascin-C, and activated matrix metalloproteinase-9, factors already implicated in human PAH. Finally, assessment of steady state mRNA showed that whereas expression of ET_B receptors was decreased in MCT^sl/sl rat lungs, ET_A receptor expression increased.

Conclusions— Deficiency of the ET_B receptor markedly accelerates the progression of PAH in rats treated with MCT and enhances the appearance of cellular and molecular markers associated with the pathobiology of PAH. Collectively, these results suggest an overall antiproliferative effect of the ET_B receptor in pulmonary vascular homeostasis.

Key Words: arteriosclerosis • endothelin • metalloproteinases • nitric oxide • pediatrics

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