THBS4 Regulates Pulmonary Hypertension via TGF-β/SMAD2 Signaling

BACKGROUND: Pulmonary hypertension (PH) is a progressive disease marked by pulmonary arterial remodeling and right ventricular dysfunction. The molecular mechanisms driving this remodeling, particularly ECM (extracellular matrix)-mediated processes, remain poorly understood. This study investigates THBS4 (thrombospondin-4), an ECM glycoprotein, as a key regulator of pulmonary vascular remodeling in pulmonary hypertension. METHODS: Whole-transcriptomic analysis was conducted on pulmonary arteries from rat models of pulmonary hypertension induced by hypoxia, hypoxia-SUGEN, and monocrotaline. THBS4 expression was measured in these models and in serum and lung tissue from patients with pulmonary arterial hypertension. The role of HIF-1α (hypoxia-inducible factor 1-alpha), SMAD2 (mothers against decapentaplegic homolog 2), and p38 MAPK (mitogen-activated protein kinase) signaling pathways in regulating THBS4 was explored. Functional assays assessed THBS4's impact on pulmonary artery smooth muscle cells. In vivo, THBS4 silencing was performed to evaluate its effect on vascular remodeling and right ventricular hypertrophy. RESULTS: THBS4 was upregulated in pulmonary arteries across all pulmonary hypertension models, with expression correlating with disease severity. Elevated THBS4 levels were observed in pulmonary arterial hypertension patient serum and lung tissue. Hypoxia-induced THBS4 expression was mediated by HIF-1α, while TGF (transforming growth factor)-β1 stimulation enhanced THBS4 via SMAD2 and p38 MAPK pathways. THBS4 promoted pulmonary artery smooth muscle cell proliferation, phenotypic modulation, and ECM remodeling. In vivo silencing of THBS4 attenuated pulmonary vascular remodeling and right ventricular hypertrophy. CONCLUSIONS: Our findings identify THBS4 as a central regulator in a self-reinforcing THBS4-TGF-β/SMAD2 signaling axis driving pulmonary vascular remodeling. Targeting THBS4 represents a promising therapeutic strategy to mitigate pathological vascular remodeling in pulmonary hypertension.