Extracellular retention of PDGF-B directs vascular remodeling in mouse hypoxia-induced pulmonary hypertension
| Autor: | Karin Tran-Lundmark, Erika Folestad, Bàrbara Laviña, Guillem Genové, Philip Tannenberg, Lars Muhl, Christer Betsholtz, Ya-Ting Chang, Hanna Gladh |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine endocrine system diseases Physiology Hypertension Pulmonary medicine.medical_treatment Vasodilation Vascular Remodeling Muscle Smooth Vascular Extracellular matrix Mice 03 medical and health sciences Physiology (medical) medicine Extracellular Animals Hypoxia Receptor Cells Cultured Cell Proliferation Platelet-Derived Growth Factor Lymphokines biology Chemistry Growth factor Cell Biology Hypoxia (medical) medicine.disease Pulmonary hypertension Extracellular Matrix Mice Inbred C57BL Disease Models Animal 030104 developmental biology biology.protein Cancer research Female medicine.symptom Pericytes Platelet-derived growth factor receptor Signal Transduction |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 314:L593-L605 |
| ISSN: | 1522-1504 1040-0605 |
| Popis: | 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/retmice did not develop PH, as assessed by hemodynamic parameters. Hypoxia did, however, induce vascular remodeling in Pdgfbret/retmice; but unlike the situation in controls where the remodeling led to an increased concentric muscularization of arteries, the vascular remodeling in Pdgfbret/retmice 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/retlungs, 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/retmice have unaltered hemodynamic parameters following chronic hypoxia, possibly secondary to a disorganized vascular muscularization. |
| Databáze: | OpenAIRE |
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