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Involvement of calcium-sensing receptors in hypoxia-induced vascular remodeling and pulmonary hypertension by promoting phenotypic modulation of small pulmonary arteries

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Abstract

Phenotype modulation of pulmonary artery smooth muscle cells (PASMCs) plays an important role during hypoxia-induced vascular remodeling and pulmonary hypertension (PAH). We had previously shown that calcium-sensing receptor (CaSR) is expressed in rat PASMCs. However, little is known about the role of CaSR in phenotypic modulation of PASMCs in hypoxia-induced PAH as well as the underlying mechanisms. In this study, we investigated whether CaSR induces the proliferation of PASMCs in small pulmonary arteries from both rats and human with PAH. PAH was induced by exposing rats to hypoxia for 7–21 days. The mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy index (RVI), the percentage of medial wall thickness to the external diameter (WT %), and cross-sectional total vessel wall area to the total area (WA %) of small pulmonary arteries were determined by hematoxylin and eosin (HE), masson trichrome and Weigert’s staining. The protein expressions of matrix metalloproteinase (MMP)-2 and MMP-9, the tissue inhibitors of metalloproteinase (TIMP)-3, CaSR, proliferating cell nuclear antigen (PCNA), phosphorylated extracellular signal-regulated kinase (p-ERK), and smooth muscle cell (SMC) phenotype marker proteins in rat small pulmonary arteries, including calponin, SMα-actin (SMAα), and osteopontin (OPN), were analyzed by immunohistochemistry and Western blotting, respectively. In addition, immunohistochemistry was applied to paraffin-embedded human tissues from lungs of normal human and PAH patients with chronic heart failure (PAH/CHF). Compared with the control group, mPAP, RVI, WT % and WA % in PAH rats were gradually increased with the prolonged hypoxia. At the same time, the expressions of CaSR, MMP-2, MMP-9, TIMP-3, PCNA, OPN, and p-ERK were markedly increased, while the expressions of SMAα and calponin were significantly reduced in lung tissues or small pulmonary arteries of PAH rats. Neomycin (an agonist of CaSR) enhanced but NPS2390 (an antagonist of CaSR) weakened these hypoxic effects. We further found that the expression change of CaSR, PCNA, and SMC phenotypic marker proteins in PAH/CHF lungs was similar to those in PAH rats. Our data suggest that CaSR is involved in the pulmonary vascular remodeling and PAH by promoting phenotypic modulation of small pulmonary arteries.

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Acknowledgments

This research is supported by the National Natural Science Foundation of China (No. 81070123, 81270311, 81100191, 81270273, 81200160), the Postdoctoral Research Foundation of Heilongjiang Province (LBH-Z12197), and the Foundation of Heilongjiang Educational Committee (12511618).

Conflict of Interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Pathophysiology, Harbin Medical University, Harbin, 150086, China

    Xue Peng, Hong-Xia Li, Hong-Jiang Shao, Guang-Wei Li, Jian Sun, Yu-Hui Xi, Hong-Zhu Li, Li-Na Wang, Shu-Zhi Bai, Wei-Hua Zhang, Li Zhang, Ling-Yun Wu, Rui Wang & Chang-Qing Xu

  2. Department of Forensic medicine, Harbin Medical University, Harbin, China

    Xue Peng & Hong-Jiang Shao

  3. Second Affiliated Hospital, Harbin Medical University, Harbin, China

    Xin-Yan Wang

  4. Bio-pharmaceutical Key Laboratory of Heilongjiang Province, Harbin, China

    Wei-Hua Zhang & Chang-Qing Xu

  5. Department of Pathophysiology, Qiaihar Medical University, Qiqihar, China

    Guang-Wei Li

  6. Mudanjiang Medical College, Mudanjiang, China

    Jian Sun

  7. School of Kinesiology, Lakehead University, Thunder Bay, ON, Canada

    Guang-dong Yang

  8. Department of Health Sciences, Lakehead University, Thunder Bay, ON, Canada

    Ling-Yun Wu

  9. Department of Biology, Lakehead University, Thunder Bay, ON, Canada

    Rui Wang

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  1. Xue Peng
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Peng, X., Li, HX., Shao, HJ. et al. Involvement of calcium-sensing receptors in hypoxia-induced vascular remodeling and pulmonary hypertension by promoting phenotypic modulation of small pulmonary arteries. Mol Cell Biochem 396, 87–98 (2014). https://doi.org/10.1007/s11010-014-2145-9

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