Chronic hypoxia promoted pulmonary arterial smooth muscle cells proliferation through upregulated calcium‐sensing receptorcanonical transient receptor potential 1/6 pathway

Abstract

Objectives Although both calcium‐sensing receptor (CaSR) and canonical transient receptor potential (TRPC) proteins contribute to chronic hypoxia (CH)‐induced pulmonary arterial smooth muscle cells (PASMCs) proliferation, the relationship between CaSR and TRPC in hypoxic PASMCs proliferation remains poorly understood. The goal of this study was to identify that CH promotes PASMCs proliferation through CaSR‐TRPC pathway. Methods Rat PASMCs were isolated and treated with CH. Cell proliferation was assessed by cell counting, CCK‐8 assay, and EdU incorporation. CaSR and TRPC expressions were determined by qPCR and Western blotting. Store‐operated Ca2+ entry (SOCE) was assessed by extracellular Ca2+ restoration. Results In PASMCs, CH enhanced the cell number, cell viability and DNA synthesis, which is accompanied by upregulated expression of CaSR, TRPC1 and TRPC6. Negative CaSR modulators (NPS2143, NPS2390) inhibited, whereas positive modulators (spermine, R568) enhanced, the CH‐induced increases in cell number, cell viability and DNA synthesis in PASMCs. Knockdown of CaSR by siRNA inhibited the CH‐induced upregulation of TRPC1 and TRPC6 and enhancement of SOCE and attenuated the CH‐induced enhancements of cell number, cell viability and DNA synthesis in PASMCs. However, neither siTRPC1 nor siTRPC6 had an effect on the CH‐induced CaSR upregulation, although both significantly attenuated the CH‐induced enhancements of cell number, cell viability and DNA synthesis in PASMCs. Conclusion These results demonstrate that upregulated CaSR‐TRPC1/6 pathway mediating PASMCs proliferation is an important pathogenic mechanism under hypoxic conditions.

Deletion of classical transient receptor potential 1, 3 and 6 alters pulmonary vasoconstriction in chronic hypoxia-induced pulmonary hypertension in mice

“…However, it should be noted that TRPC channels have previously been shown to be involved in proliferation, migration, apoptosis and pulmonary vascular remodeling in CHPH ( Lin et al, 2004 ; Malczyk et al, 2013 ; Wang et al, 2013 ; Xia et al, 2014 ; Fernandez et al, 2015 ; Smith et al, 2015 ; Xu et al, 2021 ).…”

Chronic developmental hypoxia alters rat lung immune cell transcriptomes during allergic airway inflammation

“…Additionally, while airway hyperreactivity was decreased, our scRNA‐seq count data for smooth muscle cells were not significantly different in response to CDH in either OVA‐treated or PBS‐treated rats. While no studies have investigated the role of congenital developmental hypoxia on airway smooth muscle, several studies have shown that chronic hypoxia plays a role in airway smooth muscle growth (Lee & Kang, 2019 ; Minamino et al, 2001 ; Xu et al, 2021 ). Although we were interested in assessing the differentially expressed genes and enriched pathways of smooth muscle cells to evaluate gene sets related to growth, there was an insufficient number of cells for robust analysis in our current dataset.…”