title: Involvement of calcium-sensing receptors in hypoxia-induced vascular remodeling and pulmonary hypertension by promoting phenotypic modulation of small pulmonary arteries.
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.
authors: Department of Pathophysiology, Harbin Medical University, Harbin, 150086, China.
authors: Xue
authors: X
authors: Peng
authors: Hong-Xia
authors: HX
authors: Li
authors: Hong-Jiang
authors: HJ
authors: Shao
authors: Guang-Wei
authors: GW
authors: Li
authors: Jian
authors: J
authors: Sun
authors: Yu-Hui
authors: YH
authors: Xi
authors: Hong-Zhu
authors: HZ
authors: Li
authors: Xin-Yan
authors: XY
authors: Wang
authors: Li-Na
authors: LN
authors: Wang
authors: Shu-Zhi
authors: SZ
authors: Bai
authors: Wei-Hua
authors: WH
authors: Zhang
authors: Li
authors: L
authors: Zhang
authors: Guang-Dong
authors: GD
authors: Yang
authors: Ling-Yun
authors: LY
authors: Wu
authors: Rui
authors: R
authors: Wang
authors: Chang-Qing
authors: CQ
authors: Xu
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D017208:Rats, Wistar; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D012016:Reference Values; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism; D066253:Vascular Remodeling / Q000502:physiology*
chemical_list: C095550:CASR protein, human; D018809:Proliferating Cell Nuclear Antigen; D044169:Receptors, Calcium-Sensing; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; C473605:extracellular calcium cation-sensing receptor, rat; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9