Key role of 15-LO/15-HETE in angiogenesis and functional recovery in later stages of post-stroke mice

Sci Rep. 2017 Apr 24:7:46698. doi: 10.1038/srep46698.

Abstract

This study sought to clarify the effects of 15-lipoxygenase/15-hydroxyeicosatetraenoic acid in angiogenesis and neurological functional recovery after cerebral ischaemic stroke in mice. In vivo, we performed behavioural tests to determine functional recovery after stroke. Double immunofluorescence staining of CD31 and Ki67/PCNA was performed to evaluate the effects of 15-lipoxygenase/15-hydroxyeicosatetraenoic acid on angiogenesis in an MCAO mouse model. In vitro, we investigated the effects of 15-hydroxyeicosatetraenoic acid on BMVEC proliferation and migration. Our results show that MCAO upregulates 15-lipoxygenase expression in a time-dependent manner, especially in later stages of post-stroke. We confirmed that cerebral infarct area was reduced and neurological dysfunction was gradually attenuated after stroke, while 12/15-lipoxygenase knockout mice exhibited the opposite effects. Furthermore, immunofluorescence studies revealed 15-lipoxygenase increased the proliferation of mouse brain vascular endothelial cells in a time-dependent manner, while 12/15-lipoxygenase knockout blocked these effects. Moreover, 15-hydroxyeicosatetraenoic acid promoted proliferation and tube formation in BMVECs. These results demonstrate positive influence of 15-lipoxygenase/15-hydroxyeicosatetraenoic acid in angiogenesis and neuronal recovery after ischaemic stroke in mice. We also confirmed the PI3K/Akt signalling pathway was necessary for the effects of 15-hydroxyeicosatetraenoic acid in regulation of BMVEC proliferation and migration, which may potentially be a novel target for the recovery from ischaemic stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonate 12-Lipoxygenase / genetics
  • Arachidonate 12-Lipoxygenase / metabolism*
  • Arachidonate 15-Lipoxygenase / genetics
  • Arachidonate 15-Lipoxygenase / metabolism*
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Cells, Cultured
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects
  • Hydroxyeicosatetraenoic Acids / pharmacology*
  • Infarction, Middle Cerebral Artery / genetics
  • Infarction, Middle Cerebral Artery / physiopathology*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / physiopathology*
  • Recovery of Function / drug effects*
  • Recovery of Function / genetics
  • Recovery of Function / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Time Factors

Substances

  • 12-15-lipoxygenase
  • Hydroxyeicosatetraenoic Acids
  • 15-hydroxy-5,8,11,13-eicosatetraenoic acid
  • Arachidonate 12-Lipoxygenase
  • Arachidonate 15-Lipoxygenase