Extracellular retention of PDGF-B directs vascular remodeling in mouse hypoxia-induced pulmonary hypertension
(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.
(Less)
- author
- Tannenberg, Philip ; Chang, Ya Ting ; Muhl, Lars ; Laviña, Bàrbara ; Gladh, Hanna ; Genové, Guillem ; Betsholtz, Christer ; Folestad, Erika and Tran-Lundmark, Karin LU
- organization
- publishing date
- 2018-04-01
- 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
-
- pmid:29212800
- scopus:85045511760
- 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
- 2024-08-05 16:57:03
@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}}, }