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

被引：27

作者：

Vila, Elisabet ^{[1
]}

Sole, Montse ^{[2
]}

Masip, Nuria ^{[1
]}

Puertas-Umbert, Lidia ^{[1
]}

Amaro, Sergi ^{[3
,4
]}

Paula Dantas, Ana ^{[5
]}

Unzeta, Mercedes ^{[2
]}

D'Ocon, Pilar ^{[6
]}

Maria Planas, Anna ^{[4
,7
]}

Chamorro, Angel ^{[3
,4
]}

Jimenez-Altayo, Francesc ^{[1
]}

机构：

[1] Univ Autonoma Barcelona, Inst Neurociencies, Fac Med, Dept Farmacol Terapeut & Toxicol, Bellaterra 08193, Cerdanyola Del, Spain

[2] Univ Autonoma Barcelona, Inst Neurociencies, Dept Bioquim & Biol Mol, Barcelona, Spain

[3] Univ Barcelona, Hosp Clin, Comprehens Stroke Ctr, Barcelona, Spain

[4] Inst Invest Biomed August Pi i Sunyer IDIBAPS, Area Neurociences, Barcelona, Spain

[5] Inst Invest Biomed August Pi i Sunyer IDIBAPS, Inst Clin Cardiovasc, Barcelona, Spain

[6] Univ Valencia, Fac Farm, Dept Farmacol, Valencia, Spain

[7] CSIC, IIBB, Dept Isquemia Cerebral & Neurodegeneracio, Barcelona, Spain

来源：

BIOCHEMICAL PHARMACOLOGY | 2019年 / 164卷

关键词：

Hypertension; Ischaemic stroke; Kruppel-like factor 2; Vascular endothelial growth factor-A; Blood-brain barrier; Angiogenesis; GROWTH-FACTOR; VASCULAR-PERMEABILITY; BARRIER BREAKDOWN; THERAPY IMPROVES; ISCHEMIC-STROKE; EDEMA FORMATION; ANGIOGENESIS; VEGF; NEUROPROTECTION; EXPRESSION;

D O I：

10.1016/j.bcp.2019.04.002

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 Kriippel-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.

引用

页码：115 / 128

页数：14

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