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Pulmonary Hypertension (PH) Animal Model

Pulmonary Hypertension (PH) Animal Model

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Pulmonary hypertension
Cardiovascular disease model

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Model Introduction

Model Introduction

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Pulmonary hypertension

Introduction to the PH Animal Model

Pulmonary hypertension (PH) is a refractory pulmonary vascular disease characterized by pulmonary vascular remodeling and elevated pulmonary arterial pressure. It represents a hemodynamic and pathophysiological state in which pulmonary arterial pressure exceeds a defined threshold, owing to known or unknown etiologies, and may ultimately lead to right ventricular hypertrophy, heart failure, and death.

 

 

Based on clinical, therapeutic, and pathophysiological characteristics, pulmonary arterial hypertension is classified into five groups: group 1—pulmonary arterial hypertension; group 2—pulmonary hypertension due to left heart disease; group 3—pulmonary hypertension due to lung disease or hypoxia; group 4—pulmonary hypertension due to pulmonary vascular obstruction; and group 5—pulmonary hypertension of unknown etiology. Although the underlying causes vary among these subtypes, they all share similar pathological features, including medial hypertrophy of pulmonary vessels, intimal hyperplasia and fibrosis, adventitial thickening accompanied by moderate perivascular inflammatory cell infiltration, plexiform lesions, and in situ thrombosis. Ongoing proliferation and remodeling of pulmonary vessels lead to partial occlusion, increased pulmonary vascular resistance, and progressive right‑heart failure and functional decline, ultimately resulting in death.

Currently, rodent models of pulmonary hypertension have been widely employed to investigate the pathophysiology of PH and to develop novel therapeutic strategies.

 

 

Applications of Rodents in Pulmonary Arterial Hypertension

Among these, the main methods for establishing a PH model include monocrotaline (MCT)–induced pulmonary hypertension, hypoxia‑exposure induction, injection‑based approaches, and surgical shunt procedures.

Advantages of Aniphe BioLab’s Animal Model Platform for pH Studies

This platform boasts a well-established, state-of-the-art model‑building and evaluation system for pulmonary hypertension (PH), with mature technologies and comprehensive supporting resources, enabling it to undertake a wide range of related experimental studies and drug‑development projects.

Comprehensive model coverage

There are various methods for model creation.

Common modeling approaches include administration of monocrotaline, hypoxia, and surgical shunting, with model phenotypes closely mirroring clinical presentations.

Standardization of the modeling process

The model has high stability.

The experimental procedures are standardized, yielding high animal survival and modeling rates, with minimal intra-group variability and excellent reproducibility.

Multidimensional Evaluation System

Comprehensive and thorough testing

Multidimensional assessments, including pulmonary arterial pressure measurement, echocardiography, histopathological staining, and molecular biology, can be performed.

Adapted for multi-cycle studies

Supports customized solutions

Modeling conditions and observation duration can be adjusted according to research requirements.

Standardization of Data Delivery

One-stop closed-loop service

The entire process is completed independently, with a short turnaround time, while simultaneously meeting the requirements for both basic research and regulatory compliance submissions.

Modeling cycle

Standard model cycle: 2–4 weeks

1  Laboratory animals

Mice and rats of SPF grade

1  Positive drug

Commonly used agents such as bosentan, sildenafil, and treprostinil can lower pulmonary arterial pressure, improve pulmonary vascular remodeling, and enhance right ventricular function.

1  Application areas

It is used to investigate the pathogenic mechanisms underlying pulmonary vascular remodeling, right ventricular hypertrophy, and heart failure; to screen for targeted therapies for pulmonary arterial hypertension and agents that improve right ventricular function, as well as to evaluate their efficacy and safety; and to support the identification of drug‑targeting pathways and the development of candidate compounds, thereby facilitating both basic research and preclinical studies such as IND submissions.

Different methods for establishing PH models

Bleomycin-induced model

Methylcholanthrene (MCT) is a pyrrolo‑alkane alkaloid extracted from the seeds of wild lilies, and it can induce hepatotoxicity and pulmonary arterial hypertension.

MCT model characteristics: It involves endothelial cell apoptosis and perivascular inflammation, which are analogous to the pathophysiological mechanisms underlying human pulmonary arterial hypertension. The MCT model can more effectively elucidate the process of pulmonary vascular remodeling and the critical role of inflammatory responses in its pathogenesis. Moreover, this model offers several advantages, including technical simplicity, reproducibility, short experimental duration, good stability, and low cost.

Modeling procedure: Twenty to twenty-five male SD rats were selected and randomly assigned to a control group and a model group. The model group received subcutaneous injections of monocrotaline, while the control group was administered an equivalent volume of saline; both groups were housed under identical conditions in an SPF environment and observed daily. At weeks 2 and 4 after administration, six rats from each group were sacrificed for sample collection and biomarker analysis.

 

 

Right ventricular systolic subwave pattern in rats

 

 

Echocardiographic Findings and Statistical Graphs of Rats in the Experimental Group

Following ultrasonic examination, right heart catheterization revealed that the right ventricular systolic pressure was significantly elevated in the monocrotaline-induced pulmonary hypertension group compared with the control group. Subsequently, the right ventricular mass, left ventricular mass, and interventricular septal mass were measured in the experimental rats; the results showed that, relative to the control group, the RV/(LV + S) ratio was increased in the monocrotaline‑induced pulmonary hypertension group.

 

 

HE staining of lung tissue in the experimental group rats

Compared with the control group, the model group exhibited marked alterations in pulmonary histomorphological parameters, including endothelial cell injury, uneven cellular distribution, prominent thickening of arterial walls accompanied by hyaline change, luminal narrowing of small arteries with pronounced muscularization, extensive inflammatory cell infiltration in the lung tissue, and a reduced density of pulmonary vessels.

Hypoxia-induced model

Hypoxic pulmonary hypertension is a common clinical condition, often precipitated by chronic respiratory diseases such as chronic obstructive pulmonary disease, sleep apnea, and high-altitude illness.

Chronic hypoxia can induce endothelial cell injury, leading to an imbalance of vasoactive factors, enhancing pulmonary vasoconstriction, and promoting vascular remodeling, ultimately resulting in pulmonary arterial hypertension. In recent years, research on hypoxic pulmonary vasoconstriction and pulmonary arterial remodeling has primarily focused on the endothelin‑1, nitric oxide, cyclooxygenase, and adenosine monophosphate pathways.

 

 

Modeling procedure:

1. Set the oxygen concentration in the hypoxic chamber to 10%, and select adult male C57 mice or SD rats as the experimental subjects. Establish a control group and a hypoxia group.

2. Place the hypoxic‑group mice or rats in a hypoxic chamber, leaving the lid open to ensure adequate air circulation and provide ad libitum access to food. Also, place a desiccant canister and soda lime inside the chamber to maintain appropriate humidity and CO₂ levels.

3. Monitor the mice daily, and replace the bedding, desiccant canister, and soda lime weekly. Animals in the control group are housed under identical conditions in a normoxic housing room; with the exception of the oxygen level, all other environmental parameters are the same.

4. Animals were maintained under 12-hour photoperiods and dark conditions, and after three weeks of hypoxic exposure in rats and four weeks in mice, they were euthanized to assess the pathological progression of pulmonary arterial hypertension.

Pathological HE-stained results of pulmonary arterioles in mice

 

 

Compared with the blank control group, the model‑group mice exhibited marked thickening of the pulmonary arteriolar walls, luminal narrowing, reduced interstitial space, and prominent perivascular inflammatory cell infiltration, along with evidence of vascular remodeling. Both WT% and WA% were significantly elevated, with differences reaching statistical significance (P<0.01).

Detection of α-SMA protein expression levels in lung tissue by immunofluorescence in mice

 

 

Compared with the blank control group, the model group exhibited a markedly increased α‑SMA fluorescence intensity in lung tissue and thickening of the pulmonary arteriolar smooth muscle layer; moreover, the proportion of fully muscularized small pulmonary vessels was significantly elevated, with these differences reaching statistical significance.

Pathological HE-stained results of rat pulmonary arterioles

 

 

With the prolongation of hypoxia, the walls of pulmonary arterioles in rats progressively thicken (as indicated by the black arrows in the figure), particularly with marked proliferation of medial smooth muscle cells.

Right ventricular weight and mean pulmonary arterial pressure in rats

 

 

As the duration of hypoxic exposure was prolonged, the mean pulmonary arterial pressure (mPAP) in rats increased significantly, and the ratio of right ventricular mass to total heart mass (RV/(LV+S)) also rose markedly.