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A novel rat model of pulmonary hypertension induced by mono treatment with SU5416

Hypertension Research volume 43, pages 754–764 (2020)Cite this article

Abstract

Pulmonary hypertension (PH) is responsible for premature death caused by progressive and severe heart failure. A simple, feasible, and reproducible animal model of PH is essential for the investigation of the pathogenesis and treatment of this condition. Previous studies have demonstrated that the vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor SU5416 combined with hypoxia could establish an animal model of PH. Here, we investigated whether SU5416 itself could induce PH in rats. The effects of SU5416 treatment followed by 5 weeks of normoxia were examined. Hemodynamic measurements and histological assessments of the pulmonary vasculature and the heart were conducted to evaluate the physiological and pathophysiological characteristics of PH. Compared with the control rats, the SU5416-treated rats showed significantly increased right ventricle systolic pressure, right ventricle mass, total pulmonary vascular resistance, and total pulmonary vascular resistance index, while the cardiac output and cardiac index were substantially decreased. Moreover, the degree of occlusion and the muscularization levels of the distal small pulmonary vessels and the medial wall thickness of larger vessels (OD > 50 μm) simultaneously increased. SU5416 inhibited pulmonary vascular endothelial cell apoptosis in rats, as shown by immunostaining of cleaved caspase-3. Furthermore, changes in the right ventricle, myocardial hypertrophy, myocardial edema, myocardial necrosis, striated muscle cell atrophy, vessel muscularization, neointimal occlusion, and increased collagen deposition were observed in the SU5416 group compared with the control group. Thus, treatment with SU5416 alone plus 5 weeks of normoxia could be sufficient to induce PH in rats, which may provide a good and convenient model for future investigation of PH.

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Acknowledgements

This work was supported in part by grants from the National Natural Science Foundation of China (81630004, 81800061, 81970057, 81520108001, 81770043, 81800057, 81700048, 81900046, and 81800054), the Department of Science and Technology of China Grants (2016YFC0903700, 2016YFC1304102, and 2018YFC1311900), Changjiang Scholars and Innovative Research Team in University grant IRT0961, the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01S155), Guangdong Department of Science and Technology Grants (2016A030311020, 2016A030313606, 2017A020215114, 2019A1515010615, 2019A050510046, 2019A1515010672, and 2019B030316028), a Guangzhou Department of Education Scholarship (1201630095), the Guangdong Province Universities, the Colleges Pearl River Scholar Funded Scheme of China, the Inner Mongolia Autonomous Region Science and Technology Innovation Guidance Project and the Inner Mongolia Autonomous Region Science and Technology Project (20160298), and the Independent Project of State Key Laboratory of Respiratory Disease (SKLRD-QN-201704). This work was also supported in part by the grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health (R35HL135807 and U01HL125208) and an Actelion ENTELLIGENCE Young Investigator Award.

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Author notes

  1. These authors contributed equally: Yuqin Chen, Meidan Kuang, Shiyun Liu, Chi Hou, Xin Duan

Authors and Affiliations

  1. State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China

    Yuqin Chen, Meidan Kuang, Shiyun Liu, Kai Yang, Wenjun He, Jing Liao, Qiuyu Zheng, Guofa Zou, Haixia Chen, Han Yan, Jiyuan Chen, Yi Li, Xiaoyun Luo, Qian Jiang, Haiyang Tang, Wenju Lu & Jian Wang

  2. Department of Neurology, Guangzhou Women and Children’s Medical Center, Guangzhou, China

    Chi Hou

  3. State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Xin Duan

  4. Guangdong General Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China

    Ying Zhou

  5. Department of Medicine, University of California, San Diego, La Jolla, California, USA

    Jian Wang

  6. Division of Pulmonary and Critical Care Medicine, The People’s Hospital of Inner Mongolia, Huhhot, Inner Mongolia, China

    Jian Wang

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Contributions

YC, MK, JC, GZ, HC, HY, YL, YZ and QZ performed the experiments; WH, JL, CH and QJ analyzed the data; XL and YC prepared the figures; SL and KY drafted the manuscript; WL, and JW were responsible for the conception and design of the research; YC, MK, HT, XD, GZ, and JW edited and revised the manuscript; and JW approved the final version of the manuscript.

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Correspondence to Jian Wang.

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Chen, Y., Kuang, M., Liu, S. et al. A novel rat model of pulmonary hypertension induced by mono treatment with SU5416. Hypertens Res 43, 754–764 (2020). https://doi.org/10.1038/s41440-020-0457-6

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