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Extracellular retention of PDGF-B directs vascular remodeling in mouse hypoxia-induced pulmonary hypertension
Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden;Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden.
Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden;Chang Gung Mem Hosp, Dept Pediat, Taoyuan, Taiwan.
Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
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2018 (English)In: American Journal of Physiology - Lung cellular and Molecular Physiology, ISSN 1040-0605, E-ISSN 1522-1504, Vol. 314, no 4, p. 1593-1605Article in journal (Refereed) Published
Abstract [en]

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(ret/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. Pdgfb(ret/ret) mice did not develop PH, as assessed by hemodynamic parameters. Hypoxia did, however, induce vascular remodeling in Pdgfb(ret/ret) mice; but unlike the situation in controls where the remodeling led to an increased concentric muscularization of arteries, the vascular remodeling in Pdgfb(ret/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 Pdgfb(ret/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, Pdgfb(ret/ret) mice have unaltered hemodynamic parameters following chronic hypoxia, possibly secondary to a disorganized vascular muscularization.

Place, publisher, year, edition, pages
AMER PHYSIOLOGICAL SOC , 2018. Vol. 314, no 4, p. 1593-1605
Keyword [en]
extracellular matrix, growth factor, PDGF, pulmonary hypertension, vascular remodeling
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-352716DOI: 10.1152/ajplung.00054.2017ISI: 000429466200006PubMedID: 29212800OAI: oai:DiVA.org:uu-352716DiVA, id: diva2:1215471
Funder
Swedish Research CouncilEU, European Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2018-06-08 Created: 2018-06-08 Last updated: 2018-06-08Bibliographically approved

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Laviña, BàrbaraBetsholtz, Christer

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