Neurol Res . 2017 Sep;39(9):795-802. doi: 10.1080/01616412.2017.1321710. Epub 2017 May 1.

The 15-LO-1/15-HETE system promotes angiogenesis by upregulating VEGF in ischemic brains

Li Chen  1 Yan-Mei Zhu  1 Yu-Nong Li  1 Peng-Yan Li  1 Di Wang  1 Yu Liu  1 You-Yang Qu  1 Da-Ling Zhu  2 Yu-Lan Zhu  1


  • 1 a Department of Neurology , Second Affiliated Hospital of Harbin Medical University , Harbin , China.
  • 2 b Department of Biopharmaceutical Sciences, College of Pharmacy , Harbin Medical University (Daqing) , Daqing , China.


Objectives: Angiogenesis promotes neurobehavioral recovery after cerebral ischemic stroke. 15(S)-hydroxyeicosatetraenoic acid (15-HETE) is one of the major metabolites of arachidonic acid by 15-lipoxygenase (15-LO) and stimulates the production of vascular endothelial growth factor (VEGF), thus, inducing autocrine-mediated angiogenesis. The present study aimed to investigate the role of 15-LO/15-HETE system on VEGF expression and angiogenesis in brain ischemia.

Methods: Rat cerebral arterial vascular endothelial cells were used to set up a cell injury model of oxygen-glucose deprivation and reoxygenation (OGD/R), mimicking a condition of brain ischemia. A mouse model of middle cerebral artery occlusion (MCAO) was established.

Results: Oxygen-glucose deprivation increased cellular expression of 15-LO-1 and VEGF. Transfection of 15-LO-1 siRNA depleted cells of 15-LO-1, and sequentially induced downregulation of VEGF expression; while, incubation of 15-HETE increased the expression of VEGF. Incubation of 15-HETE attenuated the reduction in cell viability induced by oxygen-glucose deprivation, and promoted cell migration, while transfection of 15-LO-1 siRNA showed an opposite effect. In animal experiments, the density of microvessels in hypoxic regions of brains was significantly increased after MCAO, while intracerebroventricular delivery of 15-LO-1 siRNA significantly reduced the density of microvessels, and downregulates VEGF expression.

Discussion: The results indicate that the 15-LO-1/15-HETE system promotes angiogenesis in ischemic brains by upregulation of VEGF, representing a potential target for improving neurobehavioral recovery after cerebral ischemic stroke.

Keywords: 15(S)-hydroxyeicosatetraenoic acid; 15-lipoxygenase; Ischemic stroke; vascular endothelial growth factor.