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

Abstract

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. 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 <i>Stc1</i>^-/- mice by hemodynamic and histological analyses, with or without intratracheal rhSTC1 administration. RNA sequencing revealed <i>STC1</i> to be a pressure-induced gene in IPAH SMCs. PIEZO1 activation upregulated <i>STC1</i>, whereas knockdown blunted this response. <i>STC1</i> was upregulated in IPAH lungs, while rhSTC1 reduced pulmonary arterial SMC proliferation and increased p-p53, p21, and p27 expression. <i>Stc1</i>^-/- 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 <i>Stc1</i>^-/- mice under normoxia and further elevated with hypoxia. Intratracheal administration of rhSTC1 attenuated PAH in wild-type and <i>Stc1</i>^-/- mice. Elevated hydrostatic pressure drives <i>STC1</i> expression via PIEZO1, suggesting an adaptive but insufficient protective response in IPAH. Modulation of STC1 (stanniocalcin-1) may represent a potential therapeutic approach.