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

Ahmad F Alghanem, Emma L Wilkinson, Maxine S Emmett, Mohammad A Aljasir, Katherine Holmes, Beverley A Rothermel, Victoria A Simms, Victoria L Heath, Michael J Cross

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)
119 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)341–358
JournalAngiogenesis
Volume20
Early online date7 Mar 2017
DOIs
Publication statusPublished - Aug 2017

Keywords

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

Fingerprint

Dive into the research topics of 'RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells'. Together they form a unique fingerprint.

Cite this