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Extracellular retention of PDGF-B directs vascular remodeling in mouse hypoxia-induced pulmonary hypertension

Tannenberg, Philip ; Chang, Ya Ting ; Muhl, Lars ; Laviña, Bàrbara ; Gladh, Hanna ; Genové, Guillem ; Betsholtz, Christer ; Folestad, Erika and Tran-Lundmark, Karin LU (2018) In American Journal of Physiology: Lung Cellular and Molecular Physiology 314(4). p.593-605
Abstract

Pulmonary hypertension (PH) is a lethal condition, and current vasodilator therapy has limited effect. Antiproliferative strategies targeting platelet-derived growth factor (PDGF) receptors, such as imatinib, have generated promising results in animal studies. Imatinib is, however, a nonspecific tyrosine kinase inhibitor and has in clinical studies caused unacceptable adverse events. Further studies are needed on the role of PDGF signaling in PH. Here, mice expressing a variant of PDGF-B with no retention motif (Pdgfbret/ret), resulting in defective binding to extracellular matrix, were studied. Following 4 wk of hypoxia, right ventricular systolic pressure, right ventricular hypertrophy, and vascular remodeling were... (More)

Pulmonary hypertension (PH) is a lethal condition, and current vasodilator therapy has limited effect. Antiproliferative strategies targeting platelet-derived growth factor (PDGF) receptors, such as imatinib, have generated promising results in animal studies. Imatinib is, however, a nonspecific tyrosine kinase inhibitor and has in clinical studies caused unacceptable adverse events. Further studies are needed on the role of PDGF signaling in PH. Here, mice expressing a variant of PDGF-B with no retention motif (Pdgfbret/ret), resulting in defective binding to extracellular matrix, were studied. Following 4 wk of hypoxia, right ventricular systolic pressure, right ventricular hypertrophy, and vascular remodeling were examined. Pdgfbret/ret mice did not develop PH, as assessed by hemodynamic parameters. Hypoxia did, however, induce vascular remodeling in Pdgfbret/ret mice; but unlike the situation in controls where the remodeling led to an increased concentric muscularization of arteries, the vascular remodeling in Pdgfbret/ret mice was characterized by a diffuse muscularization, in which cells expressing smooth muscle cell markers were found in the interalveolar septa detached from the normally muscularized intra-acinar vessels. Additionally, fewer NG2-positive perivascular cells were found in Pdgfbret/ret lungs, and mRNA analyses showed significantly increased levels of Il6 following hypoxia, a known promigratory factor for pericytes. No differences in proliferation were detected at 4 wk. This study emphasizes the importance of extracellular matrix-growth factor interactions and adds to previous knowledge of PDGF-B in PH pathobiology. In summary, Pdgfbret/ret mice have unaltered hemodynamic parameters following chronic hypoxia, possibly secondary to a disorganized vascular muscularization.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Extracellular matrix, Growth factor, PDGF, Pulmonary hypertension, Vascular remodeling
in
American Journal of Physiology: Lung Cellular and Molecular Physiology
volume
314
issue
4
pages
593 - 605
publisher
American Physiological Society
external identifiers
  • scopus:85045511760
  • pmid:29212800
ISSN
1522-1504
DOI
10.1152/ajplung.00054.2017
language
English
LU publication?
yes
id
97a9edd1-beff-4749-a563-ad34f8e15c98
date added to LUP
2018-04-27 13:36:44
date last changed
2024-04-29 08:01:07
@article{97a9edd1-beff-4749-a563-ad34f8e15c98,
  abstract     = {{<p>Pulmonary hypertension (PH) is a lethal condition, and current vasodilator therapy has limited effect. Antiproliferative strategies targeting platelet-derived growth factor (PDGF) receptors, such as imatinib, have generated promising results in animal studies. Imatinib is, however, a nonspecific tyrosine kinase inhibitor and has in clinical studies caused unacceptable adverse events. Further studies are needed on the role of PDGF signaling in PH. Here, mice expressing a variant of PDGF-B with no retention motif (Pdgfb<sup>ret/ret</sup>), resulting in defective binding to extracellular matrix, were studied. Following 4 wk of hypoxia, right ventricular systolic pressure, right ventricular hypertrophy, and vascular remodeling were examined. Pdgfb<sup>ret/ret</sup> mice did not develop PH, as assessed by hemodynamic parameters. Hypoxia did, however, induce vascular remodeling in Pdgfb<sup>ret/ret</sup> mice; but unlike the situation in controls where the remodeling led to an increased concentric muscularization of arteries, the vascular remodeling in Pdgfb<sup>ret/ret</sup> mice was characterized by a diffuse muscularization, in which cells expressing smooth muscle cell markers were found in the interalveolar septa detached from the normally muscularized intra-acinar vessels. Additionally, fewer NG2-positive perivascular cells were found in Pdgfb<sup>ret/ret</sup> lungs, and mRNA analyses showed significantly increased levels of Il6 following hypoxia, a known promigratory factor for pericytes. No differences in proliferation were detected at 4 wk. This study emphasizes the importance of extracellular matrix-growth factor interactions and adds to previous knowledge of PDGF-B in PH pathobiology. In summary, Pdgfb<sup>ret/ret</sup> mice have unaltered hemodynamic parameters following chronic hypoxia, possibly secondary to a disorganized vascular muscularization.</p>}},
  author       = {{Tannenberg, Philip and Chang, Ya Ting and Muhl, Lars and Laviña, Bàrbara and Gladh, Hanna and Genové, Guillem and Betsholtz, Christer and Folestad, Erika and Tran-Lundmark, Karin}},
  issn         = {{1522-1504}},
  keywords     = {{Extracellular matrix; Growth factor; PDGF; Pulmonary hypertension; Vascular remodeling}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{4}},
  pages        = {{593--605}},
  publisher    = {{American Physiological Society}},
  series       = {{American Journal of Physiology: Lung Cellular and Molecular Physiology}},
  title        = {{Extracellular retention of PDGF-B directs vascular remodeling in mouse hypoxia-induced pulmonary hypertension}},
  url          = {{http://dx.doi.org/10.1152/ajplung.00054.2017}},
  doi          = {{10.1152/ajplung.00054.2017}},
  volume       = {{314}},
  year         = {{2018}},
}