2. Academic Validation
  3. Upregulated Calcium Sensing Receptor Mediates Pulmonary Venous Remodeling in Pulmonary Hypertension

Upregulated Calcium Sensing Receptor Mediates Pulmonary Venous Remodeling in Pulmonary Hypertension

  • Acta Physiol (Oxf). 2026 Jan;242(1):e70142. doi: 10.1111/apha.70142.
Qiudi Mo 1 2 3,  Xing Wen 1 2,  Luyao Wang 1 2 4,  Weitao Cao 1 2 5,  Jieping Liang 1 2,  Shaoxing Li 6,  Zhenli Fu 1 2,  Xiaohua Gao 1 2,  Yan Xue 1 2,  Hong Yuan 1 2,  Zhenbo Xu 7,  Wei Hong 8,  Yumin Zhou 1 2,  Gongyong Peng 1 2
Affiliations

Affiliations

  • 1 Department of Pulmonary and Critical Care Medicine in Hengqin Hospital, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Diseases, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, Guangzhou Medical University, Guangzhou, China.
  • 2 Department of Geriatrics Medicine, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Diseases, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, Guangzhou Medical University, Guangzhou, China.
  • 3 Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 4 Henan Provincial Chest Hospital, Zhengzhou University, Zhengzhou, China.
  • 5 Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China.
  • 6 The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China.
  • 7 School of Food Science and Engineering, Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, Engineering Research Center of Starch and Vegetable Protein Processing Ministry of Education, South China University of Technology, Guangzhou, China.
  • 8 GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, China.
PMID: 41387174 DOI: 10.1111/apha.70142
Abstract

Aim: The mechanism of pulmonary venous remodeling (PVR) remains unclear. We tested the role of the calcium sensing receptor (CaSR) in PVR in pulmonary hypertension (PH).

Methods: PVR was investigated in two PH models, monocrotaline (MCT)-induced PH (MCT-PH) and hypoxia-induced PH (HPH). Human pulmonary venous smooth muscle cells (PVSMCs) were subjected to hypoxia. We examined whether CaSR is involved in the enhanced CA2+ influx and proliferation in PVSMCs and whether CaSR mediates PVR.

Results: PVR presented in distal pulmonary veins (PV) in MCT-PH and HPH rats, accompanied by upregulated CaSR expression in PVSMCs from PH rats. Hypoxia promoted human PVSMCs proliferation with increased CaSR and HIF-1α expression in hypoxic cells. Extracellular CA2+ restoration induced a huge increase in [CA2+]i in MCT-PH PVSMCs and human hypoxic PVSMCs, which was significantly higher than that in normal cells. Both the basal [CA2+]i and proliferate rate in MCT-PH PVSMCs and human hypoxic PVSMCs were higher than in normal PVSMCs. Spermine or R568 enhanced, whereas both NPS2143 or NPS2390 and siCaSR attenuated the extracellular CA2+-induced [CA2+]i increase in rat MCT-PH PVSMCs and human hypoxic PVSMCs and hypoxia-induced human PVSMCs proliferation. Blockade of CaSR with NPS2143 attenuated the increases in basal [CA2+]i in PVSMCs, right ventricular systolic pressure, and Fulton index in PH rats and prevented PVR and PH development in rats injected with MCT or exposed to hypoxia.

Conclusions: Upregulated CaSR mediating excessive PVSMCs proliferation through enhanced CaSR function and increased intracellular CA2+ signaling is an important pathogenic mechanism underlying the development of PVR in PH.

Keywords

calcium sensing receptor; pulmonary hypertension; pulmonary veins; pulmonary venous remodeling; pulmonary venous smooth muscle cells.

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