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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
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
ISSN
1040-0605
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
2019-02-20 11:15:45
@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         = {1040-0605},
  keyword      = {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},
  volume       = {314},
  year         = {2018},
}