Mechanosensitive Stanniocalcin-1 Suppresses Pulmonary Artery Smooth Muscle Cell Proliferation and Attenuates Experimental Pulmonary Hypertension

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is driven by progressive vascular remodeling, particularly smooth muscle cell (SMC) proliferation. Current combination vasodilator therapies have markedly improved outcomes; however, prognosis remains poor in subgroups such as patients with respiratory comorbidities. Elevation of intravascular hydrostatic pressure is a hallmark of IPAH, yet its direct role in pulmonary artery SMCs remains unclear. We aimed to identify pressure-responsive mediators using a newly developed hydrostatic pressurization system to model hypertensive hemodynamics. METHODS: Pulmonary artery SMCs from 4 patients with IPAH were exposed to high hydrostatic pressure (70/40 mm Hg, 60 bpm). Transcriptomic profiling identified differentially expressed genes, which were validated by quantitative polymerase chain reaction. Functional studies included PIEZO1 (piezo type mechanosensitive ion channel component 1) modulation, rhSTC1 (recombinant human stanniocalcin-1) treatment, bromodeoxyuridine incorporation, and Western blotting for cell-cycle regulators. Chronic hypoxia–induced pulmonary hypertension was assessed in wild-type and Stc1 –/– mice by hemodynamic and histological analyses, with or without intratracheal rhSTC1 administration. RESULTS: RNA sequencing revealed STC1 to be a pressure-induced gene in IPAH SMCs. PIEZO1 activation upregulated STC1 , whereas knockdown blunted this response. STC1 was upregulated in IPAH lungs, while rhSTC1 reduced pulmonary arterial SMC proliferation and increased p-p53, p21, and p27 expression. Stc1 –/– mice under hypoxia exhibited significantly higher right ventricular systolic pressure and greater pulmonary arterial medial thickness than wild-type mice. CD68-positive macrophages were increased in Stc1 –/– mice under normoxia and further elevated with hypoxia. Intratracheal administration of rhSTC1 attenuated PAH in wild-type and Stc1 –/– mice. CONCLUSIONS: Elevated hydrostatic pressure drives STC1 expression via PIEZO1, suggesting an adaptive but insufficient protective response in IPAH. Modulation of STC1 (stanniocalcin-1) may represent a potential therapeutic approach.