RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells

Research output: Contribution to journalArticle

Authors

  • Ahmad F Alghanem
  • Emma L Wilkinson
  • Maxine S Emmett
  • Mohammad A Aljasir
  • Katherine Holmes
  • Beverley A Rothermel
  • Michael J Cross

Colleges, School and Institutes

External organisations

  • University of Liverpool
  • Departments of Internal Medicine and Molecular Biology, University of Texas, Southwestern Medical Centre, Dallas, TX, USA.
  • Institute of Cardiovascular Sciences, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK.

Abstract

Regulator of calcineurin 1 (RCAN1) is an endogenous inhibitor of the calcineurin pathway in cells. It is expressed as two isoforms in vertebrates: RCAN1.1 is constitutively expressed in most tissues, whereas transcription of RCAN1.4 is induced by several stimuli that activate the calcineurin-NFAT pathway. RCAN1.4 is highly upregulated in response to VEGF in human endothelial cells in contrast to RCAN1.1 and is essential for efficient endothelial cell migration and tubular morphogenesis. Here, we show that RCAN1.4 has a role in the regulation of agonist-stimulated VEGFR-2 internalisation and establishment of endothelial cell polarity. siRNA-mediated gene silencing revealed that RCAN1 plays a vital role in regulating VEGF-mediated cytoskeletal reorganisation and directed cell migration and sprouting angiogenesis. Adenoviral-mediated overexpression of RCAN1.4 resulted in increased endothelial cell migration. Antisense-mediated morpholino silencing of the zebrafish RCAN1.4 orthologue revealed a disrupted vascular development further confirming a role for the RCAN1.4 isoform in regulating vascular endothelial cell physiology. Our data suggest that RCAN1.4 plays a novel role in regulating endothelial cell migration by establishing endothelial cell polarity in response to VEGF.

Details

Original languageEnglish
Pages (from-to)341–358
JournalAngiogenesis
Early online date7 Mar 2017
Publication statusPublished - Aug 2017

Keywords

  • VEGFR-2, RCAN1, Endothelial, Polarisation, Migration, Angiogenesis