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

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

Author information

1
Departament de Farmacologia, de Terapèutica i de Toxicologia, Facultat de Medicina, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.
2
Departament de Bioquímica i de Biologia Molecular, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
3
Comprehensive Stroke Center, Hospital Clínic, University of Barcelona, Barcelona, Spain; Àrea de Neurociènces, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
4
Institut Clínic Cardiovascular, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
5
Departamento de Farmacología, Facultad de Farmacia, Universitat de València, Valencia, Spain.
6
Àrea de Neurociènces, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Departament d'Isquèmia Cerebral i Neurodegeneració, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.
7
Departament de Farmacologia, de Terapèutica i de Toxicologia, Facultat de Medicina, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain. Electronic address: francesc.jimenez@uab.cat.

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

PMID:
30954486
DOI:
10.1016/j.bcp.2019.04.002

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