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A novel function of calcium sensing receptor in chronic hypoxia-induced pulmonary venous smooth muscle cells proliferation

Hypertension Research volume 43, pages 271–280 (2020)Cite this article

Abstract

Chronic hypoxia (CH) causes remodeling not only in pulmonary arteries but also in pulmonary veins. Pulmonary vascular remodeling stems from increased pulmonary vascular myocyte proliferation. However, the pathogenesis of CH-induced proliferation of pulmonary venous smooth muscle cells (PVSMCs) remains unknown. The present study aimed to explore the mechanisms by which CH affects PVSMCs proliferation. PVSMCs were isolated from rat distal pulmonary veins and exposed to CH (4% O2 for 60 h). The expression of calcium sensing receptor (CaSR) was determined by immunofluorescence, real-time quantitative PCR and Western blotting. Cell proliferation was assessed by cell counting, CCK-8 assay, and BrdU incorporation. Apoptosis analysis was examined by flow cytometry. In rat distal PVSMCs, CH increased the cell number and cell viability and enhanced DNA synthesis, which is accompanied by upregulated mRNA and protein expression levels of CaSR. Two negative CaSR modulators (NPS2143, NPS2390) not only attenuated CH-induced CaSR upregulation but also inhibited CH-induced increases in cell number, cell viability and the proliferation index of PVSMCs, whereas two positive modulators (spermine, R568) not only amplified CH-induced CaSR upregulation but also intensified CH-induced increases in cell number, cell viability and the proliferation index of PVSMCs. Silencing CaSR with siRNA similarly attenuated the CH-induced enhancement of cell number, cell viability and DNA synthesis in PVSMCs. Neither CH nor downregulation of CaSR with siRNA had an effect on apoptosis in PVSMCs. These results suggest that CaSR mediating excessive proliferation is a new pathogenic mechanism involved in the initiation and progression of distal PVSMCs proliferation under CH conditions.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81570045), the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01S155), the National Key Research and Development program of China (2016YFC1304100, 2016YFC1304104), the Natural Science Foundation of Guangdong Province (2017A030313683, 2017A030310419, 2016A030310107), the Science and Technology program of Guangzhou (201504010018), the Training Program for Academic Backbone of High Level Universities of Guangzhou Medical University (2017210), a grant from the First Affiliated Hospital of Guangzhou Medical University (201619), and a grant from the State Key Laboratory of Respiratory Disease (SKLRD2016ZJ013). Dr. Gongyong Peng was supported by the Overseas Scholarship of Guangzhou Medical University and the First Affiliated Hospital of Guangzhou Medical University.

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Authors and Affiliations

  1. Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China

    Shaoxing Li, Weitao Cao, Qiudi Mo, Juan Xu, Rongmin Liu, Pixin Ran & Gongyong Peng

  2. Panyu Central Hospital, Guangzhou, Guangdong, China

    Shaoxing Li

  3. GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China

    Wei Hong & Bing Li

  4. Respiratory Medicine, Hunan Provincial People’s Hospital, Changsha, Hunan, China

    Yongliang Jiang

  5. VA Palo Alto Health Care System, Stanford University School of Medicine, Palo Alto, CA, USA

    Wen Tian & Gongyong Peng

  6. Guangzhou Chest Hospital, Guangzhou, Guangdong, China

    Jinxing Hu

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Li, S., Cao, W., Hong, W. et al. A novel function of calcium sensing receptor in chronic hypoxia-induced pulmonary venous smooth muscle cells proliferation. Hypertens Res 43, 271–280 (2020). https://doi.org/10.1038/s41440-019-0373-9

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