Involvement of platelet-derived growth factor receptor β in fibrosis through extracellular matrix protein production after ischemic stroke

Exp Neurol. 2015 Feb;264:127-34. doi: 10.1016/j.expneurol.2014.12.007. Epub 2014 Dec 13.

Abstract

Fibrosis is concomitant with repair processes following injuries in the central nervous system (CNS). Pericytes are considered as an origin of fibrosis-forming cells in the CNS. Here, we examined whether platelet-derived growth factor receptor β (PDGFRβ), a well-known indispensable molecule for migration, proliferation, and survival of pericytes, was involved in the production of extracellular matrix proteins, fibronectin and collagen type I, which is crucial for fibrosis after ischemic stroke. Immunohistochemistry demonstrated induction of PDGFRβ expression in vascular cells of peri-infarct areas at 3-7days in a mouse stroke model. The PDGFRβ-expressing cells extended from peri-infarct areas toward the ischemic core after day 7 while expressing fibronectin and collagen type I in the infarct areas. In contrast, desmin and α-smooth muscle actin, markers of pericytes, were only expressed in vascular cells. In PDGFRβ heterozygous knockout mice, the expression of fibronectin and collagen type I was attenuated at both mRNA and protein levels with an enlargement of the infarct volume after ischemic stroke compared with that in wild-type littermates. In cultured brain pericytes, the expression of PDGF-B, PDGFRβ, fibronectin, and collagen type I, but not desmin, was significantly increased by serum depletion (SD). The SD-induced upregulation of fibronectin and collagen type I was suppressed by SU11652, an inhibitor of PDGFRβ, while PDGF-B further increased the SD-induced upregulation. In conclusion, the expression level of PDGFRβ may be a crucial determinant of fibrosis after ischemic stroke. Moreover, PDGFRβ signaling participates in the production of fibronectin and collagen type I after ischemic stroke.

Keywords: Collagen; Extracellular matrix; Fibroblast; Fibronectin; Fibrosis; Ischemic stroke; Pericyte; Platelet-derived growth factor receptor β.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / cytology
  • Cells, Cultured
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Extracellular Matrix Proteins / metabolism*
  • Fibrosis
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics*
  • Gene Expression Regulation / physiology
  • Indoles / pharmacology
  • Infarction, Middle Cerebral Artery / blood
  • Infarction, Middle Cerebral Artery / metabolism*
  • Infarction, Middle Cerebral Artery / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Tissue Proteins / metabolism
  • Pericytes / metabolism
  • Pyrroles / pharmacology
  • RNA, Messenger / metabolism
  • Rats
  • Receptor, Platelet-Derived Growth Factor beta / deficiency
  • Receptor, Platelet-Derived Growth Factor beta / genetics
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • Time Factors

Substances

  • Enzyme Inhibitors
  • Extracellular Matrix Proteins
  • Indoles
  • Nerve Tissue Proteins
  • Pyrroles
  • RNA, Messenger
  • SU 11652
  • Receptor, Platelet-Derived Growth Factor beta