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

We developed a cyclic hydrostatic pressurization culture system to model hypertensive hemodynamic stress in vitro and identify pressure-responsive mediators.

Methods

PASMCs from 4 patients with IPAH were exposed to high hydrostatic pressure (70/40 mmHg, 60 bpm). Transcriptomic profiling identified differentially expressed genes, validated by qPCR. Functional studies included piezo-type mechanosensitive ion channel component 1 (PIEZO1) modulation, recombinant human stanniocalcin-1 (rhSTC1) treatment, bromodeoxyuridine (BrdU) incorporation, and western blotting for cell-cycle regulators.

In vivo, 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 as a robustly pressure-induced gene in IPAH PASMCs. PIEZO1 activation upregulated STC1, whereas knockdown blunted this response.

Elevated STC1 expression was observed in PASMCs of IPAH lung tissue and rhSTC1 reduced PASMC proliferation and increased p-p53, p21, and p27 expression. In the chronic hypoxia model, Stc1–/– mice exhibited higher right ventricular systolic pressure (RVSP) (43.7 ± 1.3 vs. 30.6 ± 0.9 mmHg) and greater pulmonary arterial medial thickness (39.1 ± 2.5% vs. 26.5 ± 1.3%) than wild-type mice. CD68-positive macrophages were increased in Stc1–/– mice under normoxia and further elevated with hypoxia.

In wild-type and Stc1–/– PAH models, intratracheal administration of rhSTC1 markedly reduced medial thickening, and CD68-positive macrophage accumulation, and RVSP in both wild-type and Stc1–/– mice. Conclusions: We demonstrate, for the first time, that elevated hydrostatic pressure drives STC1 expression via PIEZO1, conferring potent anti-remodeling effects in IPAH. STC1 supplementation represents a promising therapeutic strategy that addresses an urgent medical need not fulfilled by conventional therapies.