Uric acid treatment after stroke modulates the Krüppel-like factor 2-VEGF-A axis to protect brain endothelial cell functions: Impact of hypertension

Biochem Pharmacol. 2019 Jun:164:115-128. doi: 10.1016/j.bcp.2019.04.002. Epub 2019 Apr 4.

Abstract

Uric acid (UA) is a promising protective treatment in ischaemic stroke, but the precise molecular targets underlying its in vivo beneficial actions remain unclear. High concentrations of UA inhibit angiogenesis of cultured endothelial cells via Krüppel-like factor 2 (KLF)-induced downregulation of vascular endothelial growth factor (VEGF), a pro-angiogenic mediator that is able to increase blood-brain barrier (BBB) permeability in acute stroke. Here, we investigated whether UA treatment after ischaemic stroke protects brain endothelial cell functions and modulates the KLF2-VEGF-A axis. Transient intraluminal middle cerebral artery (MCA) occlusion/reperfusion was induced in adult male spontaneously hypertensive (SHR) rats and corresponding normotensive Wistar-Kyoto (WKY) rats. Animals received UA (16 mg/kg) or vehicle (Locke's buffer) i.v. at reperfusion. BBB permeability was evaluated by Evans blue extravasation to the brain and in human cerebral endothelial hCMEC/D3 cells under oxygen-glucose deprivation/re-oxygenation. Circulating VEGF-A levels were measured in rats and acute ischaemic stroke patients from the URICO-ICTUS trial. Angiogenesis progression was assessed in Matrigel-cultured MCA. Worse post-stroke brain damage in SHR than WKY rats was associated with higher hyperaemia at reperfusion, increased Evans blue extravasation, exacerbated MCA angiogenic sprouting, and higher VEGF-A levels. UA treatment reduced infarct volume and Evans blue leakage in both rat strains, improved endothelial cell barrier integrity and KLF2 expression, and lowered VEGF-A levels in SHR rats. Hypertensive stroke patients treated with UA showed lower levels of VEGF-A than patients receiving vehicle. Consistently, UA prevented the enhanced MCA angiogenesis in SHR rats by a mechanism involving KLF2 activation. We conclude that UA treatment after ischaemic stroke upregulates KLF2, reduces VEGF-A signalling, and attenuates brain endothelial cell dysfunctions leading to neuroprotection.

Keywords: Angiogenesis; Blood-brain barrier; Hypertension; Ischaemic stroke; Krüppel-like factor 2; Vascular endothelial growth factor-A.

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Antioxidants / therapeutic use
  • Biomarkers / blood
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism*
  • Brain / drug effects
  • Brain / metabolism
  • Cell Line
  • Double-Blind Method
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Humans
  • Hypertension / blood*
  • Hypertension / drug therapy
  • Hypertension / pathology
  • Kruppel-Like Transcription Factors / agonists
  • Kruppel-Like Transcription Factors / blood*
  • Male
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred WKY
  • Stroke / blood*
  • Stroke / drug therapy
  • Stroke / pathology
  • Treatment Outcome
  • Uric Acid / pharmacology
  • Uric Acid / therapeutic use*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / blood*

Substances

  • Antioxidants
  • Biomarkers
  • Klf2 protein, rat
  • Kruppel-Like Transcription Factors
  • Neuroprotective Agents
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, rat
  • Uric Acid