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The adipokine leptin modulates adventitial pericyte functions by autocrine and paracrine signalling

Research output: Contribution to journalArticle

Original languageEnglish
Article number5443
Number of pages13
JournalScientific Reports
Volume7
DOIs
DateAccepted/In press - 6 Jun 2017
DatePublished (current) - 14 Jul 2017

Abstract

Transplantation of adventitial pericytes (APCs) improves recovery from tissue ischemia in preclinical animal models by still unknown mechanisms. This study investigates the role of the adipokine leptin (LEP) in the regulation of human APC biological functions. Transcriptomic analysis of APCs showed components of the LEP signalling pathway are modulated by hypoxia. Kinetic studies indicate cultured APCs release high amounts of immunoreactive LEP following exposure to hypoxia, continuing upon return to normoxia. Secreted LEP activates an autocrine/paracrine loop through binding to the LEP receptor (LEPR) and induction of STAT3 phosphorylation. Titration studies using recombinant LEP and siRNA knockdown of LEP or LEPR demonstrate the adipokine exerts important regulatory roles in APC growth, survival, migration and promotion of endothelial network formation. Heterogeneity in LEP expression and secretion may influence the reparative proficiency of APC therapy. Accordingly, the levels of LEP secretion predict the microvascular outcome of APCs transplantation in a mouse limb ischemia model. Moreover, we found that the expression of the Lepr gene is upregulated on resident vascular cells from murine ischemic muscles, thus providing a permissive milieu to transplanted LEP-expressing APCs. Results highlight a new mechanism responsible for APC adaptation to hypoxia and instrumental to vascular repair.

    Research areas

  • Journal Article

    Structured keywords

  • Bristol Heart Institute
  • Centre for Surgical Research

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via Nature at https://www.nature.com/articles/s41598-017-05868-y. Please refer to any applicable terms of use of the publisher.

    Final published version, 4.8 MB, PDF document

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via Nature at https://www.nature.com/articles/s41598-017-05868-y. Please refer to any applicable terms of use of the publisher.

    Final published version, 1.67 MB, PDF document

    Licence: CC BY

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