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RESEARCH PRODUCT

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

Nuria Capell MasipSergio AmaroLídia Puertas-umbertÁNgel ChamorroAna Paula DantasAnna M. PlanasFrancesc Jiménez-altayóElisabet VilaPilar D'oconMontserrat SoléMercedes Unzeta

subject

0301 basic medicineMaleVascular Endothelial Growth Factor AVascular endothelial growth factor-AAngiogenesisBiochemistryRats Inbred WKYAntioxidantschemistry.chemical_compound0302 clinical medicineRats Inbred SHRIschaemic strokeEvans BlueBlood-brain barrierBrainKrüppel-like factor 2Vascular endothelial growth factorEndothelial stem cellStrokeVascular endothelial growth factor Amedicine.anatomical_structureNeuroprotective AgentsTreatment OutcomeBlood-Brain Barrier030220 oncology & carcinogenesisHypertensioncardiovascular systemmedicine.symptommedicine.medical_specialtyKruppel-Like Transcription FactorsBrain damageBlood–brain barrierNeuroprotectionCell Line03 medical and health sciencesDouble-Blind MethodInternal medicinemedicineAnimalsHumanscardiovascular diseasesPharmacologybusiness.industryRatsUric Acid030104 developmental biologyEndocrinologychemistryEndothelium VascularAngiogenesisbusinessBiomarkers

description

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.

yearjournalcountryeditionlanguage
2019-06-01
10.1016/j.bcp.2019.04.002http://hdl.handle.net/10261/201795