Targeting the ASMase/S1P pathway protects from sortilin-evoked vascular damage in hypertension
Paola Di Pietro, … , Annibale A. Puca, Carmine Vecchione
Paola Di Pietro, … , Annibale A. Puca, Carmine Vecchione
Published February 1, 2022
Citation Information: J Clin Invest. 2022;132(3):e146343. https://doi.org/10.1172/JCI146343.
View: Text | PDF
Research Article Vascular biology

Targeting the ASMase/S1P pathway protects from sortilin-evoked vascular damage in hypertension

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.

Authors

Paola Di Pietro, Albino Carrizzo, Eduardo Sommella, Marco Oliveti, Licia Iacoviello, Augusto Di Castelnuovo, Fausto Acernese, Antonio Damato, Massimiliano De Lucia, Fabrizio Merciai, Paola Iesu, Eleonora Venturini, Raffaele Izzo, Valentina Trimarco, Michele Ciccarelli, Giuseppe Giugliano, Roberto Carnevale, Vittoria Cammisotto, Serena Migliarino, Nicola Virtuoso, Andrea Strianese, Viviana Izzo, Pietro Campiglia, Elena Ciaglia, Bodo Levkau, Annibale A. Puca, Carmine Vecchione

×
Problems with a PDF?

This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.

Having trouble reading a PDF?

PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.

Having trouble saving a PDF?

Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.

Having trouble printing a PDF?

  1. Try printing one page at a time or to a newer printer.
  2. Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
  3. Make sure you are using the latest version of Adobe's Acrobat Reader.

Supplemental data - Download (18.97 MB)

Advertisement