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Rodent Models of Group 1 Pulmonary Hypertension

  • Chapter
  • First Online:
Pharmacotherapy of Pulmonary Hypertension

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 218))

Abstract

World Health Organization category 1 pulmonary hypertension (PH) is a heterogeneous syndrome in which PH originates in the small pulmonary arteries and is therefore also referred to as pulmonary arterial hypertension (PAH). Common pathophysiologic features include endothelial dysfunction, excessive proliferation and impaired apoptosis of vascular cells, and mitochondrial fragmentation. The proliferation/apoptosis imbalance relates in part to activation of the transcription factors hypoxia-inducible factor-1α (HIF-1α) and nuclear factor of activated T-cells (NFAT) and apoptosis repressors, such as survivin. Perivascular inflammation, disruption of adventitial connective tissue, and a glycolytic metabolic shift in vascular cells and right ventricular myocytes also occur in PAH. There are important genetic and epigenetic predispositions to PAH. This review assesses the fidelity of existing animal models to human PAH. No single model can perfectly recapitulate the many diverse forms of PH in Category 1; however, acceptable models exist. PAH induced by monocrotaline and chronic hypoxia plus SU-5416 (CH+SU) in rats display endothelial dysfunction, proliferation/apoptosis imbalance, and develop the glycolytic metabolic profile of human PAH. Histologically, CH+SU best conforms to PAH in that it develops complex vascular lesions, including plexiform lesions. However, the monocrotaline model can be induced to manifest complex vascular lesions and does manifest the tendency of PAH patients to die of right ventricular (RV) failure. Murine models offer greater molecular certainty than rat models but rarely develop significant PH, have less right ventricular hypertrophy (RVH) and pulmonary artery (PA) remodeling, and are harder to image and catheterize. The use of high fidelity catheterization and advanced imaging (microPET-CT, high frequency echocardiography, high field strength MRI) and functional testing (treadmill) permit accurate phenotyping of experimental models of PAH. Preclinical trial design is an important aspect of testing experimental PAH therapies. The use of multiple complementary models with adequate sample size and trial duration and appropriate endpoints are required for preclinical assessment of experimental PAH therapies.

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Abbreviations

5-HTT:

Serotonin transporter

Ang-1:

Angiopoietin-1

BMPR-2:

Bone morphogenetic protein receptor-2

CH + SU:

Chronic hypoxia plus Sugen-5416

CO:

Cardiac output

DRP-1:

Dynamin-related protein 1

ET-1:

Endothelin-1

FHR:

Fawn-Hooded rat

HHV:

Human herpes virus

HIF-1α:

Hypoxia-inducible factor-1α

HIV:

Human immunodeficiency virus

HPV:

Hypoxic pulmonary vasoconstriction

LVEDP:

Left ventricular end diastolic pressure

mPAP:

mean pulmonary artery pressure

MRI:

Magnetic resonance imaging

NFAT:

Nuclear factor of activated T cells

PA:

Pulmonary artery

PAAT:

Pulmonary artery acceleration time

PAH:

Pulmonary arterial hypertension

PASMC:

Pulmonary artery smooth muscle cell

PDH:

Pyruvate dehydrogenase

PDK:

Pyruvate dehydrogenase kinase

PH:

Pulmonary hypertension

PVR:

Pulmonary vascular resistance

RVH:

Right ventricular hypertrophy

SOD2:

Superoxide dismutase 2

SU-5416:

Sugen-5416

TAPSE:

Tricuspid annulus plane systolic excursion

VEGF:

Vascular endothelial growth factor

VTI:

Velocity time integral

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Authors and Affiliations

  1. Cardiovascular Center, University Hospital, University of Utah, 50 N Medical Dr, Salt Lake City, UT, 84132, USA

    John J. Ryan

  2. University of Chicago, 5841 South Maryland Avenue, MC 6080, Chicago, IL, 60637, USA

    Glenn Marsboom

  3. Department of Medicine, Queen’s University, Etherington Hall, Rm. 3041, 94 Stuart Street, Kingston, ON, Canada, K7L 3N6

    Stephen L. Archer

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  1. John J. Ryan
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  2. Glenn Marsboom
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  3. Stephen L. Archer
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Correspondence to Stephen L. Archer .

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  1. Faculte´ de Me´decine, Univ Paris-Sud, Le Kremlin Bicêtre, France

    Marc Humbert

  2. Dep of Anasthesia and Critical Care, Harvard Medical School Massachusetts General Hospital, Boston, Massachusetts, USA

    Oleg V. Evgenov

  3. Cardiovascular Research, Bayer Pharma AG, Wuppertal, Germany

    Johannes-Peter Stasch

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Ryan, J.J., Marsboom, G., Archer, S.L. (2013). Rodent Models of Group 1 Pulmonary Hypertension. In: Humbert, M., Evgenov, O., Stasch, JP. (eds) Pharmacotherapy of Pulmonary Hypertension. Handbook of Experimental Pharmacology, vol 218. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-38664-0_5

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