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

Autor: Nuria Capell Masip, Sergio Amaro, Lídia Puertas-Umbert, Ángel Chamorro, Ana Paula Dantas, Anna M. Planas, Francesc Jiménez-Altayó, Elisabet Vila, Pilar D'Ocon, Montserrat Solé, Mercedes Unzeta
Přispěvatelé: Ministerio de Economía y Competitividad (España), Generalitat de Catalunya, Instituto de Salud Carlos III, European Commission, Jiménez-Altayó, Francesc [0000-0002-9034-2041], Jiménez-Altayó, Francesc
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
Vascular Endothelial Growth Factor A
Vascular endothelial growth factor-A
Angiogenesis
Biochemistry
Rats
Inbred WKY
Antioxidants
chemistry.chemical_compound
0302 clinical medicine
Rats
Inbred SHR
Ischaemic stroke
Evans Blue
Blood-brain barrier
Brain
Krüppel-like factor 2
Vascular endothelial growth factor
Endothelial stem cell
Stroke
Vascular endothelial growth factor A
medicine.anatomical_structure
Neuroprotective Agents
Treatment Outcome
Blood-Brain Barrier
030220 oncology & carcinogenesis
Hypertension
cardiovascular system
medicine.symptom
medicine.medical_specialty
Kruppel-Like Transcription Factors
Brain damage
Blood–brain barrier
Neuroprotection
Cell Line
03 medical and health sciences
Double-Blind Method
Internal medicine
medicine
Animals
Humans
cardiovascular diseases
Pharmacology
business.industry
Rats
Uric Acid
030104 developmental biology
Endocrinology
chemistry
Endothelium
Vascular
business
Biomarkers
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
instname
Popis: 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.
This work was supported by Ministerio de Ciencia e Innovación [SAF2014-56111-R]; Generalitat de Catalunya [2017-SGR-645]; Instituto Carlos III [FIS PI13/0091, RIC RD12/0042/0006]; and Instituto de Salud Carlos III (Spain) co-funded by EU FEDER funds Redes Temáticas de Investigación Cooperativa Sanitaria RETICS-INVICTUS-RD16/019.
Databáze: OpenAIRE
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