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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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 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.

Detaljer

Författare
  • Philip Tannenberg
  • Ya Ting Chang
  • Lars Muhl
  • Bàrbara Laviña
  • Hanna Gladh
  • Guillem Genové
  • Christer Betsholtz
  • Erika Folestad
  • Karin Tran-Lundmark
Enheter & grupper
Externa organisationer
  • Karolinska Institute
  • Uppsala universitet, Historiska institutionen
  • Chang Gung Memorial Hospital
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cell- och molekylärbiologi

Nyckelord

Originalspråkengelska
Sidor (från-till)L593-L605
TidskriftAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volym314
Utgivningsnummer4
StatusPublished - 2018 apr 1
PublikationskategoriForskning
Peer review utfördJa