A process-based review of mouse models of pulmonary hypertension

Abstract

Genetically modified mouse models have unparalleled power to determine the mechanisms behind different processes involved in the molecular and physiologic etiology of various classes of human pulmonary hypertension (PH). Processes known to be involved in PH for which there are extensive mouse models available include the following: (1) Regulation of vascular tone through secreted vasoactive factors; (2) regulation of vascular tone through potassium and calcium channels; (3) regulation of vascular remodeling through alteration in metabolic processes, either through alteration in substrate usage or through circulating factors; (4) spontaneous vascular remodeling either before or after development of elevated pulmonary pressures; and (5) models in which changes in tone and remodeling are primarily driven by inflammation. PH development in mice is of necessity faster and with different physiologic ramifications than found in human disease, and so mice make poor models of natural history of PH. However, transgenic mouse models are a perfect tool for studying the processes involved in pulmonary vascular function and disease, and can effectively be used to test interventions designed against particular molecular pathways and processes involved in disease.

Keywords: mouse models; pulmonary hypertension; vascular remodeling.

Figure 1

While there are a large number of mouse models of pulmonary arterial hypertension (PAH), different forms of PAH share a number of core processes. These include alterations in metabolism, inflammation, vascular tone and stiffness, vasculogenesis and intimal lesions, and conventional remodeling (muscularization, hypertrophy, adventitial thickening) (bold, black type). There are a tremendous number of PAH models (smaller colored type), which allows detailed examination of these processes, and how they interact to produce disease. There is thus not a “best”’ mouse model of PAH, but rather mouse models specialized in examining different processes of importance to the disease.

Figure 2

Graphical summary of the dysfunctional oxidative and metabolic pathways thought to be pathogenic in various models of PAH. Across the top are the various perturbations/treatments that characterize the models (e.g., Cav1 -/-, mutant BMPR2, etc.). Beneath each of these are the pathways thought to be central to the molecular pathogenesis of each model (e.g., mitochondrial dysfunction for mutant BMPR2, monocrotaline rats, and Fawn hooded rats). At the bottom are the final common pathways that are thought to lead to the PAH phenotype. Cav1 = caveolin 1; eNOS = endothelial nitric oxide synthase; NO = nitric oxide; O2- = superoxide anion; ONOO- = peroxynitrite; BMPR2 = bone morphogenetic protein receptor type 2; FHR = Fawn hooded rat, PDK = pyruvate dehydrogenase kinase, ApoE = apolipoprotein E, PPARgamma = peroxisome proliferator activated receptor gamma, PDGF = platelet-derived growth factor, PDGFR = PDGF receptor.

Figure 3

Pulmonary pathology of Fra-2 tg mice. Vascular remodeling (A) Pulmonary histology of wt mice (H and E staining, arrow indicates vascular structure, B indicates bronchus). (B) Remodelling of pulmonary vessels with luminal narrowing and obliteration in Fra-2 tg mice (arrows; H and E staining, B indicates bronchi). Adapted by permission from BMJ Publishing Group Limited. [Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis. Britta Maurer, Nicole Reich, Astrid Juengel, Jörg Kriegsmann, Renate E Gay, Georg Schett, Beat A Michel, Steffen Gay, Jörg H W Distler, Oliver Distler. 71, 1382-1387, copyright notice year 2012].