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Peer-reviewedCC BY-NC 4.0The European Respiratory Journal

Paracrine action of bone morphogenetic protein 3 in pulmonary arterial hypertension

  • Aymen Halouani1
  • Eric Mensah1
  • Mariem Ben Rhouma1
  • Zaujia Athumani1
  • Michael G. Katz2
  • Seun Imani1
  • Samar A. Antar1
  • Katherine Jankowski3
  • Maryam Mansoori3
  • Vicki Rosen4
  • Kiyotake Ishikawa2
  • Lahouaria Hadri3
1 more authors
  • Yassine Sassi1,5,6
6 affiliations
  1. 1Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, VA, USA
  2. 2Icahn School of Medicine at Mount Sinai, New York, NY, USA
  3. 3Department of Pharmacological Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  4. 4Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
  5. 5Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, USA
  6. 6Department of Internal Medicine, VTC School of Medicine, Roanoke, VA, USA
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Abstract

Background: Despite advances in therapy, pulmonary arterial hypertension (PAH) remains progressive with poor survival. Although dysregulation of bone morphogenetic protein (BMP) signalling is central to PAH, key modulators of this pathway remain incompletely defined.

Objectives: To identify the role of BMP3 in pulmonary vascular homeostasis and PAH.

Methods: BMP3 expression was assessed in experimental pulmonary hypertension and in pulmonary vascular cells and plasma from PAH patients. In vitro studies were performed in human pulmonary artery smooth muscle cells (hPASMCs) and endothelial cells (hPAECs). Global and smooth muscle cell-specific Bmp3-deficient mice were generated. Recombinant BMP3 and adeno-associated viruses (AAVs) were used to overexpress BMP3 in animal models of PAH.

Results: BMP3 is predominantly expressed in PASMCs and is consistently downregulated in experimental and human PAH. Secreted BMP3 from PAH-PASMCs and circulating BMP3 levels in PAH patients were significantly reduced. Functionally, PASMC-derived BMP3 inhibited the migration and proliferation of PAH-diseased PAECs. In both global and smooth muscle cell-specific Bmp3-deficient mice, induction of PAH led to significantly exacerbated disease in middle-aged mice. A recombinant BMP3 prevented and reversed PAH in mice. Furthermore, lung-targeted overexpression of BMP3, via AAV1-BMP3, reversed pulmonary vascular remodelling and ameliorated cardiac function in both mice and rats. Mechanistically, BMP3 restored the balance between BMP/SMAD1,5,8 and transforming growth factor (TGF)-β/SMAD2,3 signalling, and decreased the expression of cell cycle genes in PAECs.

Conclusions: BMP3 acts as a paracrine regulator of pulmonary vascular homeostasis and may contribute to the modulation of TGF-β/BMP signalling in PAH, highlighting its potential as a therapeutic target.

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Cite

BibTeXRIS
BibTeX
@article{halouani2026paracrine,
  title = {{Paracrine action of bone morphogenetic protein 3 in pulmonary arterial hypertension}},
  author = {Aymen Halouani and Eric Mensah and Mariem Ben Rhouma and Zaujia Athumani and Michael G. Katz and Seun Imani and Samar A. Antar and Katherine Jankowski and Maryam Mansoori and Vicki Rosen and Kiyotake Ishikawa and Lahouaria Hadri and Yassine Sassi},
  journal = {The European Respiratory Journal},
  year = {2026},
  month = nov,
  doi = {10.1183/13993003.02146-2025},
  url = {https://doi.org/10.1183/13993003.02146-2025},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - Paracrine action of bone morphogenetic protein 3 in pulmonary arterial hypertension
AU  - Aymen Halouani
AU  - Eric Mensah
AU  - Mariem Ben Rhouma
AU  - Zaujia Athumani
AU  - Michael G. Katz
AU  - Seun Imani
AU  - Samar A. Antar
AU  - Katherine Jankowski
AU  - Maryam Mansoori
AU  - Vicki Rosen
AU  - Kiyotake Ishikawa
AU  - Lahouaria Hadri
AU  - Yassine Sassi
PY  - 2026
DA  - 2026/11/05
JO  - The European Respiratory Journal
DO  - 10.1183/13993003.02146-2025
UR  - https://doi.org/10.1183/13993003.02146-2025
AB  - Background: Despite advances in therapy, pulmonary arterial hypertension (PAH) remains progressive with poor survival. Although dysregulation of bone morphogenetic protein (BMP) signalling is central to PAH, key modulators of this pathway remain incompletely defined.  Objectives: To identify the role of BMP3 in pulmonary vascular homeostasis and PAH.  Methods: BMP3 expression was assessed in experimental pulmonary hypertension and in pulmonary vascular cells and plasma from PAH patients. In vitro studies were performed in human pulmonary artery smooth muscle cells (hPASMCs) and endothelial cells (hPAECs). Global and smooth muscle cell-specific Bmp3-deficient mice were generated. Recombinant BMP3 and adeno-associated viruses (AAVs) were used to overexpress BMP3 in animal models of PAH.  Results: BMP3 is predominantly expressed in PASMCs and is consistently downregulated in experimental and human PAH. Secreted BMP3 from PAH-PASMCs and circulating BMP3 levels in PAH patients were significantly reduced. Functionally, PASMC-derived BMP3 inhibited the migration and proliferation of PAH-diseased PAECs. In both global and smooth muscle cell-specific Bmp3-deficient mice, induction of PAH led to significantly exacerbated disease in middle-aged mice. A recombinant BMP3 prevented and reversed PAH in mice. Furthermore, lung-targeted overexpression of BMP3, via AAV1-BMP3, reversed pulmonary vascular remodelling and ameliorated cardiac function in both mice and rats. Mechanistically, BMP3 restored the balance between BMP/SMAD1,5,8 and transforming growth factor (TGF)-β/SMAD2,3 signalling, and decreased the expression of cell cycle genes in PAECs.  Conclusions: BMP3 acts as a paracrine regulator of pulmonary vascular homeostasis and may contribute to the modulation of TGF-β/BMP signalling in PAH, highlighting its potential as a therapeutic target.
SN  - 0903-1936
SN  - 1399-3003
ER  -