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THBS4 Regulates Pulmonary Hypertension via TGF-β/SMAD2 Signaling.

Jie Zeng1, Dengyuan Li1, Jun Wang2

  • 1Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, China (J.Z., D.L., R.W., Z.H., D.S., R.L., Y.Z.).

Hypertension (Dallas, Tex. : 1979)
|March 24, 2026
PubMed
Summary

Thrombospondin-4 (THBS4) is elevated in pulmonary hypertension and drives vascular remodeling. Silencing THBS4 reduced pulmonary vascular remodeling and right ventricular hypertrophy, suggesting THBS4 as a therapeutic target.

Keywords:
SMAD2 proteinextracellular matrixhypertension, pulmonarythrombospondinstransforming growth factor betavascular remodeling

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Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Pulmonary Research

Background:

  • Pulmonary hypertension (PH) involves pulmonary arterial remodeling and right ventricular dysfunction.
  • Mechanisms of ECM-mediated remodeling in PH are poorly understood.
  • This study focuses on thrombospondin-4 (THBS4) as a regulator of pulmonary vascular remodeling.

Purpose of the Study:

  • Investigate THBS4's role in pulmonary vascular remodeling in PH.
  • Elucidate the regulatory pathways of THBS4 expression.
  • Assess THBS4's therapeutic potential in PH.

Main Methods:

  • Whole-transcriptomic analysis in rat PH models.
  • THBS4 expression analysis in patient samples.
  • Investigation of HIF-1α, SMAD2, and p38 MAPK pathways.
  • In vitro functional assays and in vivo THBS4 silencing.

Main Results:

  • THBS4 was upregulated in PH models and patients, correlating with severity.
  • HIF-1α mediated hypoxia-induced THBS4; TGF-β1 enhanced THBS4 via SMAD2/p38 MAPK.
  • THBS4 promoted smooth muscle cell proliferation and ECM remodeling.
  • THBS4 silencing attenuated vascular remodeling and right ventricular hypertrophy.

Conclusions:

  • THBS4 is a central regulator in a THBS4-TGF-β/SMAD2 signaling axis driving PH vascular remodeling.
  • Targeting THBS4 offers a potential therapeutic strategy for PH.