Targeting the ASMase/S1P pathway protects from sortilin-evoked vascular damage in hypertension.
J Clin Invest
; 132(3)2022 02 01.
Article
em En
| MEDLINE
| ID: mdl-35104805
ABSTRACT
Sortilin has been positively correlated with vascular disorders in humans. No study has yet evaluated the possible direct effect of sortilin on vascular function. We used pharmacological and genetic approaches coupled with study of murine and human samples to unravel the mechanisms recruited by sortilin in the vascular system. Sortilin induced endothelial dysfunction of mesenteric arteries through NADPH oxidase 2 (NOX2) isoform activation, dysfunction that was prevented by knockdown of acid sphingomyelinase (ASMase) or sphingosine kinase 1. In vivo, recombinant sortilin administration induced arterial hypertension in WT mice. In contrast, genetic deletion of sphingosine-1-phosphate receptor 3 (S1P3) and gp91phox/NOX2 resulted in preservation of endothelial function and blood pressure homeostasis after 14 days of systemic sortilin administration. Translating these research findings into the clinical setting, we detected elevated sortilin levels in hypertensive patients with endothelial dysfunction. Furthermore, in a population-based cohort of 270 subjects, we showed increased plasma ASMase activity and increased plasma levels of sortilin, S1P, and soluble NOX2-derived peptide (sNOX2-dp) in hypertensive subjects, and the increase was more pronounced in hypertensive subjects with uncontrolled blood pressure. Our studies reveal what we believe is a previously unrecognized role of sortilin in the impairment of vascular function and in blood pressure homeostasis and suggest the potential of sortilin and its mediators as biomarkers for the prediction of vascular dysfunction and high blood pressure.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Esfingomielina Fosfodiesterase
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Esfingosina
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Endotélio Vascular
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Lisofosfolipídeos
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Transdução de Sinais
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Proteínas Adaptadoras de Transporte Vesicular
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Hipertensão
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Clin Invest
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Itália