In Vivo Model Development for Pulmonary Arterial Hypertension

Protheragen offers comprehensive in vivo animal model development services for Pulmonary Arterial Hypertension (PAH), supporting drug discovery and translational research efforts. Our advanced platform provides a wide range of validated animal models that closely mimic the pathophysiological and clinical features of human PAH, enabling robust preclinical evaluation of therapeutic candidates.

Pulmonary Arterial Hypertension is a progressive and life-threatening disorder characterized by elevated pulmonary arterial pressure and vascular remodeling, leading to right heart failure. Animal models are indispensable in PAH research, providing critical insights into disease mechanisms, target validation, and therapeutic efficacy. Protheragen utilizes a diverse selection of species—including Macaca fascicularis (cynomolgus monkeys), minipigs (Gottingen), rats (Fischer 344, Lewis, SHR, Sprague Dawley, Wistar, ZSF1, Wistar Han, Wistar Kyoto, Wistar albino), and mice (C57/BL, C57BL/6, C57BL/6J, C57BL/6JOlaHsd, ob/ob, and various genetically modified strains). These models incorporate a range of induction methods—chemical, hypoxic, dietary, genetic, and surgical—to recapitulate the multifactorial etiology and heterogeneity of human PAH. The selection of appropriate species and strains ensures translational relevance and the ability to address specific research objectives.

Chemically-Induced Models

Chemically-induced PAH models utilize agents such as monocrotaline, sugen (SU5416), semaxanib, U-46619, endothelin-1, and bleomycin to trigger pulmonary vascular injury, remodeling, and hypertension. These models are established in mice, rats, and other species by administering the chemical agent systemically or via inhalation/injection. Key advantages include reproducibility, rapid disease onset, and well-characterized pathophysiology that closely parallels human PAH. They are especially valuable for screening drug candidates, elucidating molecular mechanisms, and studying right ventricular dysfunction.

Hypoxia-Induced and Hypobaric Models

Hypoxia-induced models expose animals to low-oxygen environments (chronic or intermittent, normobaric or hypobaric) to simulate the effects of alveolar hypoxia, a major contributor to PAH pathogenesis. These models are frequently used in mice and rats and can be combined with chemical agents for more severe phenotypes. Hypoxia-induced models are advantageous due to their clinical relevance (especially for group 3 PAH), controllability, and suitability for studying vascular remodeling and right heart adaptation. They are ideal for evaluating therapies targeting hypoxia-responsive pathways and for investigating gene-environment interactions.

Genetic and Transgenic Models

Genetic models employ knockout, knock-in, transgenic, or mutated animals to replicate hereditary or molecularly defined forms of PAH. Examples include BMPR2-mutated, Apoe-knockout, Ptger1/2/3/4, Ptgir, Fhit, ALDH2, Egln1, Map3k3, and PDGFRB transgenic mice, as well as Ccr2 knockout and Nfu1 mutated rats. These models allow for precise investigation of gene function, disease modifiers, and the impact of specific molecular pathways in PAH development. Their main advantages are the ability to dissect genetic contributions to disease and to test targeted therapies in a mechanistically defined context.

Dietary and Metabolic Models

Dietary and metabolic models involve interventions such as high-fat diet feeding, diet restriction during pregnancy, or use of genetically obese strains (e.g., ob/ob mice) to induce metabolic disturbances that contribute to PAH. These models are crucial for studying the interplay between metabolic syndrome, obesity, and pulmonary vascular disease, reflecting an increasingly recognized clinical phenotype. They are particularly useful for evaluating drugs targeting metabolic or inflammatory pathways and for understanding comorbidities in PAH.

Surgical and Physical Intervention Models

Surgical models, such as pulmonary artery occlusion, aorto-caval shunt, pneumonectomy, and exercise-induced PAH, simulate mechanical or hemodynamic stress leading to pulmonary hypertension. These approaches are essential for modeling specific clinical scenarios, such as post-thromboembolic PAH or congenital heart disease-associated PAH. Advantages include the ability to study the effects of increased flow or pressure and to evaluate device-based or interventional therapies.

Protheragen provides an end-to-end solution for PAH model development, encompassing model selection, protocol optimization, induction and monitoring of disease, therapeutic administration, and comprehensive endpoint analysis. Key efficacy endpoints include right ventricular systolic pressure (RVSP), mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy (Fulton index), pulmonary vascular resistance, echocardiography, hemodynamic measurements, histopathological assessment of vascular remodeling, and biomarker analysis. Our analytical capabilities extend to molecular profiling (qPCR, Western blot, RNA-seq), immunohistochemistry, imaging (micro-CT, MRI), and flow cytometry. Quality control is ensured through rigorous standard operating procedures, validated protocols, and continuous monitoring of animal health and model fidelity. Our experienced team provides detailed reporting, data interpretation, and ongoing technical support to facilitate successful preclinical studies.

By partnering with Protheragen, clients gain access to a comprehensive suite of validated PAH animal models, expert scientific guidance, and state-of-the-art analytical resources. Our commitment to scientific rigor, translational relevance, and customized service ensures that your PAH research and drug development programs are positioned for success. Contact us today to discuss your project needs and discover how our in vivo model development services can accelerate your path to breakthrough therapies.