Resistin‐Like Molecule Beta Participates in Calcium Regulation Via Direct Interaction With CaSR and a PLC‐IP 3 R‐Dependent Mechanism in Hypoxia‐Induced Pulmonary Hypertension

ABSTRACT The proliferation of pulmonary artery smooth muscle cells (PASMCs) is a key mechanism in hypoxic pulmonary hypertension (HPH). Resistin‐like Molecule Beta (RELM‐β) promotes the hypoxia‐induced proliferation of PASMCs, and calcium ions (Ca²⁺) play an important role in cell proliferation. However, the mechanism by which RELM‐β regulates Ca²⁺ and the pathogenesis of HPH remain unclear. We established a RELM‐β‐knockout (RELM‐β −/− ) model and assessed the mechanism by which RELM‐β affects Ca 2+ regulation, cell proliferation, and pulmonary haemodynamics. In the rat HPH model and hypoxia‐treated PASMCs, the expression of RELM‐β was increased, which led to changes in pulmonary haemodynamics (elevated right ventricular systolic pressure [RVSP], right ventricular hypertrophy, and pulmonary artery thickening) and PASMC proliferation. Conversely, after RELM‐β knockout, the opposite effects were observed. RELM‐β regulated the intracellular Ca²⁺ concentration ([Ca²⁺] i ) through the Phospholipase C‐Inositol 1,4,5‐Trisphosphate Receptor (PLC‐IP 3 R) pathway, which promoted the release of intracellular Ca²⁺ and its binding to calcium‐sensing receptor (CaSR), ultimately increasing store‐operated calcium entry (SOCE) and extracellular Ca²⁺ influx and promoting PASMC proliferation. RELM‐β, which is a cytokine‐like growth factor, plays a role in the proliferation of PASMCs and the promotion of HPH.