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Exploring the Impact of Platelet-Derived Growth Factor D in Pulmonary Hypertension Development

Tannenberg, Philip LU ; Tran-Lundmark, Karin LU ; Chang, Ya Ting ; Gladh, Hanna ; Ning, Frank Chenfei ; Westöö, Christian LU ; Norvik, Christian LU ; Alajbegovic, Azra LU ; Albinsson, Sebastian LU and Brunnström, Hans LU orcid , et al. (2025) In Pulmonary Circulation 15(4).
Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening condition with no cure, making research into its underlying mechanisms critical. The platelet-derived growth factor (PDGF) signaling pathway plays a crucial role in vascular remodeling, a key factor in PAH progression. Anti-PDGF receptor therapies, such as imatinib, show promise but are associated with significant side effects. Recent research identified PDGF-D as a new risk gene in idiopathic PAH, highlighting the need for further investigation into the PDGF pathway in the disease. In this study, we investigated PDGF-D, a specific PDGFRβ ligand, as a potential therapeutic target. RNA-Seq data from healthy lungs indicated that PDGF-D is predominantly expressed in inflammatory... (More)

Pulmonary arterial hypertension (PAH) is a life-threatening condition with no cure, making research into its underlying mechanisms critical. The platelet-derived growth factor (PDGF) signaling pathway plays a crucial role in vascular remodeling, a key factor in PAH progression. Anti-PDGF receptor therapies, such as imatinib, show promise but are associated with significant side effects. Recent research identified PDGF-D as a new risk gene in idiopathic PAH, highlighting the need for further investigation into the PDGF pathway in the disease. In this study, we investigated PDGF-D, a specific PDGFRβ ligand, as a potential therapeutic target. RNA-Seq data from healthy lungs indicated that PDGF-D is predominantly expressed in inflammatory cells, whereas in vascular lesions of idiopathic PAH patients, PDGF-D was produced by various cell types. In vitro, PDGF-D induced mitogenic effects on pulmonary arterial smooth muscle cells. However, genetic deletion of PDGF-D in the chronic hypoxia mouse model of pulmonary hypertension showed no significant impact on vascular muscularization, hemodynamic parameters, or right ventricular hypertrophy. But, the absence of hypoxia-induced Pdgfrb upregulation and the lack of increased expression of PAH-regulated genes, Fgf2 and Notch3, in PDGF-D-deficient mice, suggests activation of alternative mechanisms. MicroRNA analyses revealed PDGF-D-related alterations in the expression of miR-21 and miR-451, both important regulators in PAH, further supporting the notion that PDGF-D plays a unique role in PAH development. Taken together, our data suggest that PDGF-D may target a distinct population of PDGFRβ-expressing cells, separate from those stimulated by PDGF-B, positioning PDGF-D as a potentially unique and compelling therapeutic target for PAH.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cellular signaling, growth factors, pulmonary vascular disease, vascular remodeling
in
Pulmonary Circulation
volume
15
issue
4
article number
e70216
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:105023426450
ISSN
2045-8932
DOI
10.1002/pul2.70216
language
English
LU publication?
yes
id
a4b6f8a5-25c1-425a-a6e7-03bb83e46b4c
date added to LUP
2026-02-02 10:58:33
date last changed
2026-02-02 10:59:14
@article{a4b6f8a5-25c1-425a-a6e7-03bb83e46b4c,
  abstract     = {{<p>Pulmonary arterial hypertension (PAH) is a life-threatening condition with no cure, making research into its underlying mechanisms critical. The platelet-derived growth factor (PDGF) signaling pathway plays a crucial role in vascular remodeling, a key factor in PAH progression. Anti-PDGF receptor therapies, such as imatinib, show promise but are associated with significant side effects. Recent research identified PDGF-D as a new risk gene in idiopathic PAH, highlighting the need for further investigation into the PDGF pathway in the disease. In this study, we investigated PDGF-D, a specific PDGFRβ ligand, as a potential therapeutic target. RNA-Seq data from healthy lungs indicated that PDGF-D is predominantly expressed in inflammatory cells, whereas in vascular lesions of idiopathic PAH patients, PDGF-D was produced by various cell types. In vitro, PDGF-D induced mitogenic effects on pulmonary arterial smooth muscle cells. However, genetic deletion of PDGF-D in the chronic hypoxia mouse model of pulmonary hypertension showed no significant impact on vascular muscularization, hemodynamic parameters, or right ventricular hypertrophy. But, the absence of hypoxia-induced Pdgfrb upregulation and the lack of increased expression of PAH-regulated genes, Fgf2 and Notch3, in PDGF-D-deficient mice, suggests activation of alternative mechanisms. MicroRNA analyses revealed PDGF-D-related alterations in the expression of miR-21 and miR-451, both important regulators in PAH, further supporting the notion that PDGF-D plays a unique role in PAH development. Taken together, our data suggest that PDGF-D may target a distinct population of PDGFRβ-expressing cells, separate from those stimulated by PDGF-B, positioning PDGF-D as a potentially unique and compelling therapeutic target for PAH.</p>}},
  author       = {{Tannenberg, Philip and Tran-Lundmark, Karin and Chang, Ya Ting and Gladh, Hanna and Ning, Frank Chenfei and Westöö, Christian and Norvik, Christian and Alajbegovic, Azra and Albinsson, Sebastian and Brunnström, Hans and Hedin, Ulf and Folestad, Erika}},
  issn         = {{2045-8932}},
  keywords     = {{cellular signaling; growth factors; pulmonary vascular disease; vascular remodeling}},
  language     = {{eng}},
  number       = {{4}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Pulmonary Circulation}},
  title        = {{Exploring the Impact of Platelet-Derived Growth Factor D in Pulmonary Hypertension Development}},
  url          = {{http://dx.doi.org/10.1002/pul2.70216}},
  doi          = {{10.1002/pul2.70216}},
  volume       = {{15}},
  year         = {{2025}},
}