Submitted on July 1, 2009
Revised on September 2, 2009
Accepted on September 4, 2009
ANIMAL MODELS OF PULMONARY ARTERIAL HYPERTENSION The Hope for Etiologic Discovery and Pharmacologic Cure
Kurt R. Stenmark1*, Barbara Meyrick2, Nazzareno Galie3, Wolter J. Mooi4, and Ivan F. McMurtry5
1 University of Colorado Denver
2 Vanderbilt University Medical Center
3 Institute of Cardiology, University of Bologna
4 VU Medical Centre, The Netherlands
5 Uni of South Alabama
* To whom correspondence should be addressed. E-mail: kurt.stenmark{at}ucdenver.edu.
At present, six groups of chronic pulmonary hypertension (PH) are described. Among these, group 1 (and 1') comprises a group of diverse diseases termed pulmonary arterial hypertension (PAH) that have several pathophysiological, histological and prognostic features in common. PAH is a particulary severe and progressive form of PH that frequently leads to right heart failure and premature death. The diagnosis of PAH must include a series of defined clinical parameters, which extend beyond mere elevations in pulmonary arterial pressures and include precapillary PH, pulmonary hypertensive arteriopathy (usually with plexiform lesions), slow clinical onset (months, years) and a chronic time course (years) characterized by progressive deterioration. What appears to distinguish PAH from other forms of PH is the severity of the arteriopathy observed, the defining characteristic of which is "plexogenic arteriopathy." The pathogenesis of this arteriopathy remains unclear despite intense investigation in a variety of animal model systems. The most commonly used animal models ("classic" models) are rodents exposed to either hypoxia or monocrotaline. Newer models, which involve modification of classic approaches, have been developed which exhibit more severe PH and vascular lesions which include neointimal proliferation and occlusion of small vessels. In addition, genetically manipulated mice have been generated which have provided insight into the role of specific molecules in the pulmonary hypertensive process. Unfortunately, at present there is no perfect pre-clinical model that completely recapitulates human PAH. All models, however, have provided and will continue to provide invaluable insight into the numerous pathways that contribute to the development and maintenance of PH. Utilization of both "classic" and newly developed animal models will allow continued rigorous testing of new hypotheses regarding pathogenesis and treatment. This review highlights progress that has been made in animal modeling of this important human condition.
