Novel Role of Calcium-Sensitive Receptors in Chronic Hypoxia-Induced Proliferation of Pulmonary Vein Smooth Muscle Cells

Abstract

Objective: Vascular remodeling due to chronic hypoxia (CH) occurs not only in the pulmonary arteries but also in the pulmonary veins. Pulmonary vascular remodeling arises from the proliferation of pulmonary vascular myocytes. However, the mechanism by which CH induces the proliferation of pulmonary vein smooth muscle cells (PVSMCs) is unknown. This study aimed to investigate the mechanism by which CH affects the proliferation of PVSMCs. Methods: PVSMCs were isolated from rat distal pulmonary veins and exposed to CH (4% O₂, 60h), and the expression of the calcium-sensitive receptor (CaSR) was detected by Western blotting and immunofluorescence. MTT assay was used to detect the proliferation viability of the cells, and the changes in the intracellular calcium concentration were detected by laser confocal scanning technique. Results: CaSR expression was present in rat distal PVSMCs, and CaSR protein expression was upregulated under hypoxia. The positive regulator spermine not only enhanced CH-induced CaSR upregulation but also enhanced CH-induced increase in cell viability and calcium ion concentration. The negative CaSR regulator NPS2143 not only attenuated CH-induced CaSR upregulation but also inhibited CH-induced cell viability and calcium ion concentration. Conclusion: CaSR-mediated hyperproliferation is a novel pathogenic mechanism for the development of proliferation in distal PVSMCs under CH conditions.