PDGF/MEK/ERK axis represses Ca2+ clearance via decreasing the abundance of plasma membrane Ca2+ pump PMCA4 in pulmonary arterial smooth muscle cells

Abstract

Pulmonary arterial hypertension (PAH) is a rare and lethal disease characterized by vascular remodeling and vasoconstriction, which is associated with increased intracellular calcium ion concentration ([Ca2+]i). Platelet-derived growth factor-BB (PDGF-BB) is the most potent mitogen for pulmonary arterial smooth muscle cells (PASMCs) and is involved in vascular remodeling during PAH development. PDGF signaling has been proved to participate in maintaining Ca2+ homeostasis of PASMCs; however, the mechanism needs to be further elucidated. Here, we illuminate that the expression of plasma membrane calcium-transporting ATPase 4 (PMCA4) was downregulated in PASMCs after PDGF-BB stimulation, which could be abolished by restraining the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK). Functionally, suppression of PMCA4 attenuated the [Ca2+]i clearance in PASMCs after Ca2+ entry, promoting cell proliferation and elevating cell locomotion through mediating formation of focal adhesion. Additionally, the expression of PMCA4 was decreased in the pulmonary artery of monocrotaline (MCT)- or hypoxia-induced PAH rats. Moreover, knockdown of PMCA4 could increase the right ventricular systolic pressure (RVSP) and wall thickness (WT) of pulmonary artery in rats raised under normal conditions. Taken together, our findings demonstrate the importance of the PDGF/MEK/ERK/PMCA4 axis in intracellular Ca2+ homeostasis in PASMCs, indicating a functional role of PMCA4 in pulmonary arterial remodeling and PAH development.