Effects of angiotensin-II on brain endothelial cell permeability via PPARalpha regulation of para- and trans-cellular pathways.
Brain Res
; 1722: 146353, 2019 11 01.
Article
em En
| MEDLINE
| ID: mdl-31356784
ABSTRACT
Angiotensin-II (Ang-II) is a key factor in hypertension, diabetes and aging, which are all primary risk factors for CNS disease. Furthermore, Ang-II may play under-appreciated roles in neurogenesis, angiogenesis and CNS remodeling. Therefore, any contemplated attempts for neurorestorative therapies in the CNS should consider the context of Ang-II signaling. Here, we investigate how Ang-II may regulate cerebral endothelial permeability, a key functional feature of the neurovascular unit. Exposure of human brain endothelial cell cultures to Ang-II increased its permeability to BSA-Alexa488 tracer. Immunocytochemistry and pulse-chase experiments suggested that both para-cellular as well as trans-cellular pathways were involved. Candesartan but not PD123319 blocked Ang-II permeability effects, suggesting that Ang-II effects may be mediated via type 1 receptor. Immunocytochemistry and western blots showed that Ang-II disrupted the membrane distributions of ZO-1 and VE-Cad, decreased total levels of JAM-A and Mfsd2a, and increased Cav1. These effects of Ang-II were accompanied by dephosphorylation of PPARalpha. Finally, Ang-II-induced increases in endothelial permeability were ameliorated by PPARalpha agonists. Taken together, these studies suggest that Ang-II may disrupt both para- and trans-cellular permeability in cerebral endothelium, and PPARalpha-related pathways may offer potential therapeutic targets for ameliorating these effects in cell-based regenerative medicine.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Encéfalo
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Permeabilidade Capilar
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Angiotensina II
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Células Endoteliais
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PPAR alfa
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article